Hepatitis B capsid assembly modulators

ABSTRACT

Described herein are hepatitis B capsid assembly modulators and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of hepatitis B.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application Ser.No. 62/683,557 filed Jun. 11, 2018 and U.S. Provisional Application Ser.No. 62/832,734 filed Apr. 11, 2019 which are hereby incorporated byreference in their entirety.

BACKGROUND OF THE INVENTION

The present invention relates to small-molecule compounds that modulatecapsid assembly and block hepatitis B virus (HBV) replication with thepotential to be used as a monotherapy or in combination with otherantivirals for the treatment of chronic HBV infection.

HBV is a small enveloped DNA virus belonging to the Hepadnaviridaefamily that is distributed worldwide as ten geographically distinctgenotypes. Infection with HBV is typically self-limiting in otherwisehealthy adults; however, vertical transmission or exposure during earlychildhood often results in a chronic lifelong infection. Worldwide thereare an estimated >400 million individuals chronically infected with HBVthat are at risk for complications due to liver disease, includingcirrhosis, fibrosis, hepatocellular carcinoma and death. Each year500,000 to 1 million people die from end stage liver disease as aconsequence of HBV infection

The compact HBV genome utilizes four overlapping reading frames toencode the major structural and non-structural proteins: polymerase (F),envelope (S), core (C) and the X protein (X). HBV enters humanhepatocytes via receptor mediated endocytosis, following binding of theenvelope glycoprotein to its primary receptor, the bile acid transportersodium taurocholate co-transporting polypeptide (NTCP). Following fusionwith the endosome membrane, the capsid is ejected into the cytoplasm andtranslocated to the nucleus. The partially double-stranded, relaxed,circular HBV genome (RC DNA) is converted to a covalently closedcircular DNA form (cccDNA) by host cellular DNA repair mechanisms. TheHBV cccDNA serves as the template for RNA polymerase II-dependenttranscription of multiple RNA species, including viral mRNAs and the3.2-kbp pre-genomic RNA (pgRNA). During the maturation process, pgRNA ispackaged into capsids along with the HBV polymerase. The pgRNA is thenreverse transcribed into a negative-stranded DNA template that issubsequently converted into the partially double-stranded RC DNA speciesby the polymerase. Mature, enveloped HBV particles containing the RC DNAgenome are secreted from the surface of the infected hepatocyte ready toinitiate new cycles of infection.

The capsid is composed of 240 copies of the core protein thatspontaneously self-assemble through a network of weak inter-subunitinteractions. In vitro evidence suggests that a trimer of core dimersinitiates the nucleation event that rapidly recruits additional dimersto form the icosahedral core structure (T=4). In addition to itsstructural role, encapsidation of the pgRNA is an essential steprequired for HBV DNA synthesis and formation of the mature capsidparticle. The core protein also plays an important role in shuttling theRC DNA into the nucleus to initiate and maintain the cccDNA pools andmay also play a role in regulating interferon sensitive gene expression.Thus, capsid modulators may have the unique ability to intervene atmultiple points in the HBV lifecycle.

Several chemotype series of HBV capsid assembly modulators have beenreported in the literature including: phenylpropenamides (PP) (e.g.,AT-130), heteroarylpyrimidines (HAP) (e.g. Bay 41-4109), andsulfamoylbenzamides (SBA) (e.g. NVR 3-778). Capsid modulators exerttheir effects on the assembly process through one of two differentmechanisms of action. The HAP series induces the aberrant assembly oflarge capsid aggregates that subsequently triggers the degradation ofthe core protein. The PP and SBA series, on the other hand, appear toaccelerate capsid assembly resulting in the production of authenticempty capsid particles that have failed to incorporate pgRNA. Assemblymodulators representing both mechanisms have demonstrated the ability toreduce HBV DNA levels in mouse models of infection. More recently, NVR3-778 (SBA) demonstrated clinical proof-of-concept in a Phase 1bclinical trial, resulting in a −1.7 log 10 reduction in HBV DNAfollowing 600 mg bid dosing for 29 days.

SUMMARY OF THE INVENTION

Described herein are compounds of Formula (I), (Ia)-(Id) that modulatethe normal capsid assembly of hepatitis B core proteins to inhibit thehepatitis B lifecycle, and thus act as antiviral agents toward HBV.

Disclosed herein are compounds of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

wherein:

-   Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;-   each R¹¹ is independently halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c), —NHS(═O)₂R^(a),    —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),    —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl),    —C₁-C₆alkyl(cycloalkyl), or —C₁-C₆alkyl(heterocycloalkyl); wherein    each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl is independently optionally substituted with one,    two, or three R¹;-   or two R¹¹ on adjacent atoms are taken together with the atoms to    which they are attached to form a cycloalkyl, heterocycloalkyl,    aryl, or heteroaryl; each optionally substituted with one, two, or    three R²;-   R¹² is hydrogen or C₁-C₆alkyl;-   R¹³ is hydrogen, halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c), —NHS(═O)₂R^(a),    —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),    —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl),    —C₁-C₆alkyl(cycloalkyl), or —C₁-C₆alkyl(heterocycloalkyl); wherein    each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl is independently optionally substituted with one,    two, or three R³;-   R¹⁴ is hydrogen, halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c), —NHS(═O)₂R^(a),    —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),    —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl),    —C₁-C₆alkyl(cycloalkyl), or —C₁-C₆alkyl(heterocycloalkyl); wherein    each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl is independently optionally substituted with one,    two, or three R⁴;-   R¹⁵ is hydrogen, —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(b)R^(c),    —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl),    or —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,    alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is    independently optionally substituted with one, two, or three R⁵;-   or R¹⁴ and R¹⁵ are taken together to form a heterocycloalkyl    optionally substituted with one, two, three, or four R⁶;-   R¹⁶ and R¹⁷ are each independently hydrogen, —CN, —OR²⁰, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,    heterocycloalkenyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),    —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or    —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one, two, or three R⁷;-   or R¹⁶ and R¹⁷ are taken together with the nitrogen atom to which    they are attached to form a heterocycloalkyl or a    heterocycloalkenyl; each optionally substituted with one, two, or    three R⁸;-   each R²⁰ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one, two, or    three R⁷;-   n is 0-4;-   each R¹, R², R³, R⁴, R⁵, R⁶, and R⁸ is independently oxo, halogen,    —CN, —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂,    —NR^(b)R^(c), —NHS(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —C(═O)R^(a),    —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(b)R^(c),    —OC(═O)NR^(b)R^(c), —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),    —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or    —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one, two, or three oxo, halogen, —CN,    —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me,    —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    or C₁-C₆aminoalkyl;-   each R⁷ is independently oxo, halogen, —CN, —OH, —OR^(a), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c),    —NHS(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —B(OR^(b))(OR^(c)), —C(═O)R^(a),    —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(b)R^(c),    —OC(═O)NR^(b)R^(c), —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),    —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or    —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one, two, or three R^(7a);-   each R^(7a) is independently oxo, halogen, —CN, —OH, —OR^(a),    —NR^(b)R^(c), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(b)R^(c),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each    alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is    independently optionally substituted with one, two, or three oxo,    halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂, —S(═O)₂NH₂,    —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;-   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one, two, or    three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂,    —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl; and-   each R^(b) and R^(c) are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,    aryl, and heteroaryl is independently optionally substituted with    one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me,    —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;-   or R^(b) and R^(c) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me,    —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl.

Also disclosed herein are pharmaceutical compositions comprising acompound disclosed herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, and a pharmaceutically acceptableexcipient.

Also disclosed herein are methods of treating an infection in a subject,comprising administering to the subject a compound disclosed herein, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof ora pharmaceutical composition disclosed herein. In some embodiments of amethod of treating an infection; the infection is a viral infection. Insome embodiments of a method of treating an infection; the infection iscaused by the hepatitis B virus. In some embodiments of a method oftreating an infection; the infection is hepatitis B.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

Chronic hepatitis B infection (CHB) is currently managed withinterferon-alpha or nucleoside(tide) analog-based therapies that targetthe HBV encoded polymerase/reverse transcriptase. The effectiveness ofinterferon-alpha is limited by inadequate long term responses and severeside effects, while entecavir and tenofovir, are generallywell-tolerated, possess a high barrier to resistance and potentlysuppress viral replication. None of the aforementioned frontlinetherapies are curative, however, and expensive lifelong therapy isrequired to maintain a virologic response and prevent the complicationsassociated with liver disease. Novel therapies representing differenttreatment classes are therefore urgently required to improve functionalcure rates (i.e. defined as the loss of HBsAg expression) and shortentreatment durations. Modulators of HBV capsid assembly represent onesuch class of antivirals with the potential to improve outcomes forchronically infected individuals.

Definitions

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Furthermore, theparticular features, structures, or characteristics may be combined inany suitable manner in one or more embodiments. Also, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“oxo” refers to ═O.

“Alkyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain saturated hydrocarbon monoradicalhaving from one to about ten carbon atoms, more preferably one to sixcarbon atoms. Examples include, but are not limited to methyl, ethyl,n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, suchas heptyl, octyl and the like. Whenever it appears herein, a numericalrange such as “C₁-C₆ alkyl” or “C₁₋₆alkyl”, means that the alkyl groupmay consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbonatoms, 5 carbon atoms or 6 carbon atoms, although the present definitionalso covers the occurrence of the term “alkyl” where no numerical rangeis designated. In some embodiments, the alkyl is a C₁₋₁₀alkyl. In someembodiments, the alkyl is a C₁₋₆alkyl. In some embodiments, the alkyl isa C₁₋₅alkyl. In some embodiments, the alkyl is a C₁₋₄alkyl. In someembodiments, the alkyl is a C₁₋₃alkyl. Unless stated otherwisespecifically in the specification, an alkyl group may be optionallysubstituted as described below, for example, with oxo, halogen, amino,nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, thealkyl is optionally substituted with oxo, halogen, —CN, —OH, —OMe, —NH₂,or —NO₂. In some embodiments, the alkyl is optionally substituted withhalogen, —CN, —OH, or —OMe. In some embodiments, the alkyl is optionallysubstituted with halogen.

“Alkenyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon double-bonds and having from two to about tencarbon atoms, more preferably two to about six carbon atoms. The groupmay be in either the cis or trans conformation about the double bond(s),and should be understood to include both isomers. Examples include, butare not limited to ethenyl (—CH═CH₂), 1-propenyl (—CH₂CH═CH₂),isopropenyl [—C(CH₃)═CH₂], butenyl, 1,3-butadienyl and the like.Whenever it appears herein, a numerical range such as “C₂-C₆ alkenyl” or“C₂₋₆alkenyl”, means that the alkenyl group may consist of 2 carbonatoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms,although the present definition also covers the occurrence of the term“alkenyl” where no numerical range is designated. Unless statedotherwise specifically in the specification, an alkenyl group may beoptionally substituted as described below, for example, with oxo,halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, the alkenyl is optionally substituted with oxo, halogen,—CN, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, the alkenyl isoptionally substituted with halogen, —CN, —OH, or —OMe. In someembodiments, the alkenyl is optionally substituted with halogen.

“Alkynyl” refers to an optionally substituted straight-chain oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon triple-bonds and having from two to about tencarbon atoms, more preferably from two to about six carbon atoms.Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl,1,3-butadiynyl and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkynyl” or “C₂₋₆alkynyl”, means that the alkynylgroup may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5carbon atoms or 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkynyl” where no numerical range isdesignated. Unless stated otherwise specifically in the specification,an alkynyl group may be optionally substituted as described below, forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Insome embodiments, the alkynyl is optionally substituted with oxo,halogen, —CN, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, the alkynylis optionally substituted with halogen, —CN, —OH, or —OMe. In someembodiments, the alkynyl is optionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain.Unless stated otherwise specifically in the specification, an alkylenegroup may be optionally substituted as described below, for example,with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy,aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, the alkylene is optionally substituted with oxo, halogen,—CN, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, the alkylene isoptionally substituted with halogen, —CN, —OH, or —OMe. In someembodiments, the alkylene is optionally substituted with halogen.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted asdescribed below, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, the alkoxy is optionallysubstituted with halogen, —CN, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the alkoxy is optionally substituted with halogen, —CN,—OH, or —OMe. In some embodiments, the alkoxy is optionally substitutedwith halogen.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused (when fused with acycloalkyl or heterocycloalkyl ring, the aryl is bonded through anaromatic ring atom) or bridged ring systems. In some embodiments, thearyl is a 6- to 10-membered aryl. In some embodiments, the aryl is a6-membered aryl (phenyl). Aryl radicals include, but are not limited to,aryl radicals derived from the hydrocarbon ring systems of anthrylene,naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene,fluoranthene, fluorene, as-indacene, s-indacene, indane, indene,naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. Unless stated otherwise specifically in the specification,an aryl may be optionally substituted as described below, for example,with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, andthe like. In some embodiments, the aryl is optionally substituted withhalogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the aryl is optionally substituted with halogen, methyl,ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, the aryl isoptionally substituted with halogen.

“Cycloalkyl” refers to a stable, partially or fully saturated,monocyclic or polycyclic carbocyclic ring, which may include fused (whenfused with an aryl or a heteroaryl ring, the cycloalkyl is bondedthrough a non-aromatic ring atom) or bridged ring systems.Representative cycloalkyls include, but are not limited to, cycloalkylshaving from three to fifteen carbon atoms (C₃-C₁₅ cycloalkyl), fromthree to ten carbon atoms (C₃-C₁₀ cycloalkyl), from three to eightcarbon atoms (C₃-C₈ cycloalkyl), from three to six carbon atoms (C₃-C₆cycloalkyl), from three to five carbon atoms (C₃-C₅ cycloalkyl), orthree to four carbon atoms (C₃-C₄ cycloalkyl). In some embodiments, thecycloalkyl is a 3- to 10-membered cycloalkyl. In some embodiments, thecycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, thecycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkylsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, forexample, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane,bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, andbicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partiallysaturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically inthe specification, a cycloalkyl is optionally substituted, for example,with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl,alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, a cycloalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, a cycloalkyl is optionallysubstituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe.In some embodiments, the cycloalkyl is optionally substituted withhalogen.

“Cycloalkenyl” refers to a partially unsaturated, monocyclic orpolycyclic carbocyclic ring, which may include fused (when fused with anaryl or a heteroaryl ring, the cycloalkenyl is bonded through anon-aromatic ring atom) or bridged ring systems. Representativecycloalkenyl include, but are not limited to, cycloalkenyls having fromthree to fifteen carbon atoms (C₃-C₁₅ cycloalkenyl), from three to tencarbon atoms (C₃-C₁₀ cycloalkenyl), from three to eight carbon atoms(C₃-C₈ cycloalkenyl), from three to six carbon atoms (C₃-C₆cycloalkenyl), from three to five carbon atoms (C₃-C₅ cycloalkenyl),four to six carbon atoms (C₄-C₆ cycloalkenyl), four to eight carbonatoms (C₄-C₈ cycloalkenyl), or four to ten carbon atoms (C₄-C₁₀cycloalkenyl). Monocyclic cycloalkenyl include, for example,cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,cyclohexadiene, cycloheptadiene, and cycloheptatriene. Unless statedotherwise specifically in the specification, a cycloalkenyl may beoptionally substituted as described below, for example, with oxo,halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, andthe like. In some embodiments, the cycloalkenyl is optionallysubstituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe,—NH₂, or —NO₂. In some embodiments, the cycloalkenyl is optionallysubstituted with halogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. Insome embodiments, the cycloalkenyl is optionally substituted withhalogen.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In someembodiments, halogen is fluoro or chloro. In some embodiments, halogenis fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like.

“Heterocycloalkyl” refers to a stable 3- to 24-membered fully saturatedring radical comprising 2 to 23 carbon atoms and from one to 8heteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur. In some embodiments, the heterocycloalkylcomprises one to three heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkylcomprises one to three heteroatoms selected from the group consisting ofnitrogen and oxygen. In some embodiments, the heterocycloalkyl comprisesone to three nitrogens. In some embodiments, the heterocycloalkylcomprises one or two nitrogens. In some embodiments, theheterocycloalkyl comprises one nitrogen. In some embodiments, theheterocycloalkyl comprises one nitrogen and one oxygen. Unless statedotherwise specifically in the specification, the heterocycloalkylradical may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which may include fused (when fused with an aryl or a heteroarylring, the heterocycloalkyl is bonded through a non-aromatic ring atom)or bridged ring systems; and the nitrogen, carbon, or sulfur atoms inthe heterocycloalkyl radical may be optionally oxidized; the nitrogenatom may be optionally quaternized. Representative heterocycloalkylsinclude, but are not limited to, heterocycloalkyls having from two tofifteen carbon atoms (C₂-C₁₅ heterocycloalkyl), from two to ten carbonatoms (C₂-C₁₀ heterocycloalkyl), from two to eight carbon atoms (C₂-C₈heterocycloalkyl), from two to seven carbon atoms (C₂-C₇heterocycloalkyl), from two to six carbon atoms (C₂-C₆heterocycloalkyl), from two to five carbon atoms (C₂-C₅heterocycloalkyl), or two to four carbon atoms (C₂-C₄ heterocycloalkyl).Examples of such heterocycloalkyl radicals include, but are not limitedto, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl,methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The termheterocycloalkyl also includes all ring forms of the carbohydrates,including but not limited to the monosaccharides, the disaccharides andthe oligosaccharides. Unless otherwise noted, heterocycloalkyls havefrom 2 to 10 carbons in the ring. It is understood that when referringto the number of carbon atoms in a heterocycloalkyl, the number ofcarbon atoms in the heterocycloalkyl is not the same as the total numberof atoms (including the heteroatoms) that make up the heterocycloalkyl(i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments,the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In someembodiments, the heterocycloalkyl is a 3- to 7-memberedheterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to6-membered heterocycloalkyl. In some embodiments, the heterocycloalkylis a 4- to 6-membered heterocycloalkyl. In some embodiments, theheterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Unless statedotherwise specifically in the specification, a heterocycloalkyl may beoptionally substituted as described below, for example, with oxo,halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, andthe like. In some embodiments, the heterocycloalkyl is optionallysubstituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe,—NH₂, or —NO₂. In some embodiments, the heterocycloalkyl is optionallysubstituted with halogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. Insome embodiments, the heterocycloalkyl is optionally substituted withhalogen.

“Heterocycloalkenyl” refers to a stable 3- to 24-membered partiallyunsaturated ring radical comprising 2 to 23 carbon atoms and from one to8 heteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur. In some embodiments, the heterocycloalkenylcomprises one to three heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur. In some embodiments, theheterocycloalkenyl comprises one to three heteroatoms selected from thegroup consisting of nitrogen and oxygen. In some embodiments, theheterocycloalkenyl comprises one to three nitrogens. In someembodiments, the heterocycloalkenyl comprises one or two nitrogens. Insome embodiments, the heterocycloalkenyl comprises one nitrogen. Unlessstated otherwise specifically in the specification, theheterocycloalkenyl may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused (when fused with anaryl or a heteroaryl ring, the heterocycloalkyl is bonded through anon-aromatic ring atom) or bridged ring systems; and the nitrogen,carbon or sulfur atoms in the heterocycloalkenyl radical may beoptionally oxidized; the nitrogen atom may be optionally quaternized.Representative heterocycloalkenyls include, but are not limited to,heterocycloalkenyls having from two to ten carbon atoms (C₂-C₁₀heterocycloalkenyl), from two to eight carbon atoms (C₂-C₈heterocycloalkenyl), from two to seven carbon atoms (C₂-C₇heterocycloalkenyl), from two to six carbon atoms (C₂-C₆heterocycloalkenyl), from two to five carbon atoms (C₂-C₅heterocycloalkenyl), or two to four carbon atoms (C₂-C₄heterocycloalkenyl). Examples of such heterocycloalkenyls include, butare not limited to, 2,3-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine,1,2-dihydropyridine, 1,2,3,4-tetrahydropyrazine, and3,4-dihydro-2H-1,4-oxazine. Unless otherwise noted, heterocycloalkenylshave from 2 to 10 carbons in the ring. It is understood that whenreferring to the number of carbon atoms in a heterocycloalkenyl, thenumber of carbon atoms in the heterocycloalkenyl is not the same as thetotal number of atoms (including the heteroatoms) that make up theheterocycloalkenyl (i.e. skeletal atoms of the heterocycloalkenyl ring).In some embodiments, the heterocycloalkenyl is a 3- to 8-memberedheterocycloalkenyl. In some embodiments, the heterocycloalkenyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, theheterocycloalkenyl is a 3- to 6-membered heterocycloalkenyl. In someembodiments, the heterocycloalkenyl is a 4- to 6-memberedheterocycloalkenyl. In some embodiments, the heterocycloalkenyl is a 5-to 6-membered heterocycloalkenyl. Unless stated otherwise specificallyin the specification, a heterocycloalkenyl may be optionally substitutedas described below, for example, with oxo, halogen, amino, nitrile,nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, the heterocycloalkenyl is optionally substituted with oxo,halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the heterocycloalkenyl is optionally substituted withhalogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments,the heterocycloalkenyl is optionally substituted with halogen.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. In someembodiments, the heteroaryl comprises one to three heteroatoms selectedfrom the group consisting of nitrogen, oxygen, and sulfur. In someembodiments, the heteroaryl comprises one to three heteroatoms selectedfrom the group consisting of nitrogen and oxygen. In some embodiments,the heteroaryl comprises one to three nitrogens. In some embodiments,the heteroaryl comprises one or two nitrogens. In some embodiments, theheteroaryl comprises one nitrogen. The heteroaryl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused (when fused with a cycloalkyl or heterocycloalkyl ring,the heteroaryl is bonded through an aromatic ring atom) or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. In some embodiments, the heteroaryl is a 5- to 10-memberedheteroaryl. In some embodiments, the heteroaryl is a 5- to 6-memberedheteroaryl. In some embodiments, the heteroaryl is a 6-memberedheteroaryl. In some embodiments, the heteroaryl is a 5-memberedheteroaryl. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl may be optionallysubstituted as described below, for example, with halogen, amino,nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy,aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, the heteroaryl is optionally substituted with halogen,methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments,the heteroaryl is optionally substituted with halogen, methyl, ethyl,—CN, —CF₃, —OH, or —OMe. In some embodiments, the heteroaryl isoptionally substituted with halogen.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc.). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,000 daltons, and more typically, up to about 500daltons.

An “effective amount” or “therapeutically effective amount” refers to anamount of a compound administered to a mammalian subject, either as asingle dose or as part of a series of doses, which is effective toproduce a desired therapeutic effect.

“Treatment” of an individual (e.g. a mammal, such as a human) or a cellis any type of intervention used in an attempt to alter the naturalcourse of the individual or cell. In some embodiments, treatmentincludes administration of a pharmaceutical composition, subsequent tothe initiation of a pathologic event or contact with an etiologic agentand includes stabilization of the condition (e.g., condition does notworsen) or alleviation of the condition. In some embodiments, treatmentalso includes prophylactic treatment (e.g., administration of acomposition described herein when an individual is suspected to besuffering from a viral infection, e.g., hepatitis B).

Compounds

Described herein are compounds of Formula (I), (Ia)-(Id), or apharmaceutically acceptable salt, solvate, or stereoisomer thereofuseful in the treatment of viral infections. In some embodiments, theviral infection is a chronic hepatitis B infection.

Disclosed herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

wherein:

-   Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;-   each R¹¹ is independently halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c), —NHS(═O)₂R^(a),    —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),    —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl),    —C₁-C₆alkyl(cycloalkyl), or —C₁-C₆alkyl(heterocycloalkyl); wherein    each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl is independently optionally substituted with one,    two, or three R¹;-   or two R¹¹ on adjacent atoms are taken together with the atoms to    which they are attached to form a cycloalkyl, heterocycloalkyl,    aryl, or heteroaryl; each optionally substituted with one, two, or    three R²;-   R¹² is hydrogen or C₁-C₆alkyl;-   R¹³ is hydrogen, halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c), —NHS(═O)₂R^(a),    —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),    —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl),    —C₁-C₆alkyl(cycloalkyl), or —C₁-C₆alkyl(heterocycloalkyl); wherein    each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl is independently optionally substituted with one,    two, or three R³;-   R¹⁴ is hydrogen, halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c), —NHS(═O)₂R^(a),    —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),    —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl),    —C₁-C₆alkyl(cycloalkyl), or —C₁-C₆alkyl(heterocycloalkyl); wherein    each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl is independently optionally substituted with one,    two, or three R⁴;-   R¹⁵ is hydrogen, —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(b)R^(c),    —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl),    or —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,    alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is    independently optionally substituted with one, two, or three R⁵;-   or R¹⁴ and R¹⁵ are taken together to form a heterocycloalkyl    optionally substituted with one, two, three, or four R⁶;-   R¹⁶ and R¹⁷ are each independently hydrogen, —CN, —OR²⁰, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,    heterocycloalkenyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),    —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or    —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one, two, or three R⁷;-   or R¹⁶ and R¹⁷ are taken together with the nitrogen atom to which    they are attached to form a heterocycloalkyl or a    heterocycloalkenyl; each optionally substituted with one, two, or    three R⁸;-   each R²⁰ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one, two, or    three R⁷;-   n is 0-4;-   each R¹, R², R³, R⁴, R⁵, R⁶, and R⁸ is independently oxo, halogen,    —CN, —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂,    —NR^(b)R^(c), —NHS(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —C(═O)R^(a),    —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(b)R^(c),    —OC(═O)NR^(b)R^(c), —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),    —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or    —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one, two, or three oxo, halogen, —CN,    —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me,    —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    or C₁-C₆aminoalkyl;-   each R⁷ is independently oxo, halogen, —CN, —OH, —OR^(a), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c),    —NHS(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —B(OR^(b))(OR^(c)), —C(═O)R^(a),    —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(b)R^(c),    —OC(═O)NR^(b)R^(c), —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),    —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or    —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one, two, or three R^(7a);-   each R^(7a) is independently oxo, halogen, —CN, —OH, —OR^(a),    —NR^(b)R^(c), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(b)R^(c),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each    alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is    independently optionally substituted with one, two, or three oxo,    halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂, —S(═O)₂NH₂,    —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;-   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one, two, or    three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂,    —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl; and-   each R^(b) and R^(c) are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,    aryl, and heteroaryl is independently optionally substituted with    one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me,    —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;-   or R^(b) and R^(c) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me,    —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl.    -   In some embodiment of a compound of Formula (I), R¹⁴ is        hydrogen, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),        —C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, or        cycloalkyl.

Disclosed herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

wherein:

-   Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;-   each R¹¹ is independently halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c), —NHS(═O)₂R^(a),    —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),    —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl),    —C₁-C₆alkyl(cycloalkyl), or —C₁-C₆alkyl(heterocycloalkyl); wherein    each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl is independently optionally substituted with one,    two, or three R¹;-   or two R¹¹ on adjacent atoms are taken together with the atoms to    which they are attached to form a cycloalkyl, heterocycloalkyl,    aryl, or heteroaryl; each optionally substituted with one, two, or    three R²;-   R¹² is hydrogen or C₁-C₆alkyl;-   R¹³ is hydrogen, halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c), —NHS(═O)₂R^(a),    —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),    —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl),    —C₁-C₆alkyl(cycloalkyl), or —C₁-C₆alkyl(heterocycloalkyl); wherein    each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl is independently optionally substituted with one,    two, or three R³;-   R¹⁴ is hydrogen, halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c), —NHS(═O)₂R^(a),    —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),    —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl),    —C₁-C₆alkyl(cycloalkyl), or —C₁-C₆alkyl(heterocycloalkyl); wherein    each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl is independently optionally substituted with one,    two, or three R⁴;-   R¹⁵ is hydrogen, —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(b)R^(c),    —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl),    or —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,    alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is    independently optionally substituted with one, two, or three R⁵;-   or R¹⁴ and R¹⁵ are taken together to form a heterocycloalkyl    optionally substituted with one, two, three, or four R⁶;-   R¹⁶ and R¹⁷ are each independently hydrogen, —CN, —OR²⁰, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl),    or —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,    alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is    independently optionally substituted with one, two, or three R⁷;-   or R¹⁶ and R¹⁷ are taken together with the nitrogen atom to which    they are attached to form a heterocycloalkyl or a    heterocycloalkenyl; each optionally substituted with one, two, or    three R⁸;-   each R²⁰ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one, two, or    three R⁷;-   n is 0-4;-   each R¹, R², R³, R⁴, R⁵, R⁶, and R⁸ is independently oxo, halogen,    —CN, —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂,    —NR^(b)R^(c), —NHS(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —C(═O)R^(a),    —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(b)R^(c),    —OC(═O)NR^(b)R^(c), —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),    —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or    —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one, two, or three oxo, halogen, —CN,    —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me,    —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    or C₁-C₆aminoalkyl;-   each R⁷ is independently oxo, halogen, —CN, —OH, —OR^(a), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c),    —NHS(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —B(OR^(b))(OR^(c)), —C(═O)R^(a),    —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(b)R^(c),    —OC(═O)NR^(b)R^(c), —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),    —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or    —C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one, two, or three R^(7a);-   each R^(7a) is independently oxo, halogen, —CN, —OH, —OR^(a),    —NR^(b)R^(c), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(b)R^(c),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;-   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one, two, or    three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂,    —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl; and-   each R^(b) and R^(c) are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,    aryl, and heteroaryl is independently optionally substituted with    one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me,    —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;-   or R^(b) and R^(c) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me,    —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl.    -   In some embodiment of a compound of Formula (I), R¹⁴ is        hydrogen, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),        —C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, or        cycloalkyl.

In some embodiment of a compound of Formula (I), R¹⁴ is hydrogen,halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one, two, or three R⁴. In some embodiment of a compound of Formula(I), R¹⁴ is hydrogen, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;wherein each alkyl is independently optionally substituted with one,two, or three R⁴. In some embodiment of a compound of Formula (I), R¹⁴is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl; wherein each alkyl is independently optionallysubstituted with one, two, or three R⁴. In some embodiment of a compoundof Formula (I), R¹⁴ is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl;wherein each alkyl is independently optionally substituted with one,two, or three R⁴. In some embodiment of a compound of Formula (I), R¹⁴is hydrogen, halogen, C₁-C₆alkyl optionally substituted with one, two,or three R⁴. In some embodiment of a compound of Formula (I), R¹⁴ ishydrogen or C₁-C₆alkyl. In some embodiment of a compound of Formula (I),R¹⁴ is C₁-C₆alkyl.

In some embodiment of a compound of Formula (I), each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl in R¹⁴ is optionally substitutedwith one, two, or three R⁴. In some embodiment of a compound of Formula(I), each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl inR¹⁴ is optionally substituted with one or two R⁴. In some embodiment ofa compound of Formula (I), each alkyl, cycloalkyl, heterocycloalkyl,aryl, and heteroaryl in R¹⁴ is optionally substituted with one R⁴. Insome embodiment of a compound of Formula (I), each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl in R¹⁴ is optionally substitutedwith two R⁴. In some embodiment of a compound of Formula (I), eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl in R¹⁴ isoptionally substituted with three R⁴.

In some embodiment of a compound of Formula (I), each R⁴ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),—C(═O)R^(a), —C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiment of a compound of Formula (I), eachR⁴ is independently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;wherein each alkyl is independently optionally substituted with one,two, or three oxo, halogen, —CN, —OH, —OMe, —NH₂, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiment of a compound of Formula (I), each R⁴is independently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl; wherein each alkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiment of acompound of Formula (I), each R⁴ is independently oxo, halogen, —CN,—OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl. In someembodiment of a compound of Formula (I), each R⁴ is independently oxo,halogen, —CN, —OH, —OMe, —NH₂, Me, or CF₃. In some embodiment of acompound of Formula (I), each R⁴ is independently halogen.

In some embodiment of a compound of Formula (I), R¹⁵ is hydrogen,—S(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one, two, or three R⁵. In some embodiment of a compound of Formula(I), R¹⁵ is hydrogen, —S(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl; wherein each alkyl isindependently optionally substituted with one, two, or three R⁵. In someembodiment of a compound of Formula (I), R¹⁵ is hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl; wherein eachalkyl is independently optionally substituted with one, two, or threeR⁵. In some embodiment of a compound of Formula (I), R¹⁵ is hydrogen,—S(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orcycloalkyl. In some embodiment of a compound of Formula (I), R¹⁵ ishydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆hydroxyalkyl. In someembodiment of a compound of Formula (I), R¹⁵ is hydrogen, C₁-C₆alkyl, orC₁-C₆hydroxyalkyl. In some embodiment of a compound of Formula (I), R¹⁵is hydrogen or C₁-C₆alkyl. In some embodiment of a compound of Formula(I), R¹⁵ is C₁-C₆alkyl.

In some embodiment of a compound of Formula (I), each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl in R¹⁵ is optionally substitutedwith one, two, or three R⁵. In some embodiment of a compound of Formula(I), each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl inR¹⁵ is optionally substituted with one or two R⁵. In some embodiment ofa compound of Formula (I), each alkyl, cycloalkyl, heterocycloalkyl,aryl, and heteroaryl is R¹⁵ in optionally substituted with one R. Insome embodiment of a compound of Formula (I), each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl in R¹⁵ is optionally substitutedwith two R⁵. In some embodiment of a compound of Formula (I), eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl in R¹⁵ isoptionally substituted with three R⁵.

In some embodiment of a compound of Formula (I), each R⁵ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),—C(═O)R^(a), —C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiment of a compound of Formula (I), eachR⁵ is independently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;wherein each alkyl is independently optionally substituted with one,two, or three oxo, halogen, —CN, —OH, —OMe, —NH₂, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiment of a compound of Formula (I), each R⁵is independently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl; wherein each alkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiment of acompound of Formula (I), each R⁵ is independently oxo, halogen, —CN,—OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl. In someembodiment of a compound of Formula (I), each R⁵ is independently oxo,halogen, —CN, —OH, —OMe, —NH₂, Me, or CF₃. In some embodiment of acompound of Formula (I), each R⁵ is independently halogen.

In some embodiment of a compound of Formula (I), R¹⁴ and R¹⁵ are takentogether to form a heterocycloalkyl optionally substituted with one,two, three, or four R⁶. In some embodiment of a compound of Formula (I),R¹⁴ and R¹⁵ are taken together to form a heterocycloalkyl optionallysubstituted with one, two, three, or four R⁶; wherein theheterocycloalkyl is a 5-, 6-, or 7-membered heterocycloalkyl.

In some embodiment of a compound of Formula (I), R¹⁴ and R¹⁵ are takentogether to form a heterocycloalkyl optionally substituted with one,two, three, or four R⁶; wherein the heterocycloalkyl is a 5-memberedheterocycloalkyl. In some embodiment of a compound of Formula (I), R¹⁴and R¹⁵ are taken together to form a heterocycloalkyl optionallysubstituted with one, two, three, or four R⁶; wherein theheterocycloalkyl is a 6-membered heterocycloalkyl. In some embodiment ofa compound of Formula (I), R¹⁴ and R¹⁵ are taken together to form aheterocycloalkyl optionally substituted with one, two, three, or fourR⁶; wherein the heterocycloalkyl is a 7-membered heterocycloalkyl.

In some embodiment of a compound of Formula (I), the heterocycloalkylformed when R¹⁴ and R¹⁵ are taken together is optionally substitutedwith one, two, or three R⁶. In some embodiment of a compound of Formula(I), the heterocycloalkyl formed when R¹⁴ and R¹⁵ are taken together isoptionally substituted with one or two R⁶. In some embodiment of acompound of Formula (I), the heterocycloalkyl formed when R¹⁴ and R¹⁵are taken together is optionally substituted with one R⁶. In someembodiment of a compound of Formula (I), the heterocycloalkyl formedwhen R¹⁴ and R¹⁵ are taken together is optionally substituted with twoR⁶. In some embodiment of a compound of Formula (I), theheterocycloalkyl formed when R¹⁴ and R¹⁵ are taken together isoptionally substituted with three R⁶.

In some embodiment of a compound of Formula (I), each R⁶ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),—C(═O)R^(a), —C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiment of a compound of Formula (I), eachR⁶ is independently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;wherein each alkyl is independently optionally substituted with one,two, or three oxo, halogen, —CN, —OH, —OMe, —NH₂, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiment of a compound of Formula (I), each R⁶is independently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl; wherein each alkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiment of acompound of Formula (I), each R⁶ is independently oxo, halogen, —CN,—OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl. In someembodiment of a compound of Formula (I), each R⁶ is independentlyhalogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), —S(═O)₂R^(a),—S(═O)₂NR^(b)R^(c), —C(═O)R^(a), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, or cycloalkyl. In some embodiment of a compound ofFormula (I), each R⁶ is independently halogen —S(═O)₂R^(a), —C(═O)R^(a),or C₁-C₆alkyl. In some embodiment of a compound of Formula (I), each R⁶is independently oxo, halogen, —CN, —OH, —OMe, —NH₂, Me, or CF₃. In someembodiment of a compound of Formula (I), each R⁶ is independentlyhalogen.

In some embodiment of a compound of Formula (I),

In some embodiment of a compound of Formula (I),

is

In some embodiment of a compound of Formula (Ia), each R⁶ isindependently halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), —S(═O)₂R^(a),—S(═O)₂NR^(b)R^(c), —C(═O)R^(a), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, or cycloalkyl. In some embodiment of a compound ofFormula (Ia), each R⁶ is independently halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), —S(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or cycloalkyl. In some embodiment ofa compound of Formula (Ia), each R⁶ is independently halogen, —OH,—S(═O)₂R^(a), —C(═O)R^(a), or C₁-C₆alkyl. In some embodiment of acompound of Formula (Ia), each R⁶ is independently halogen,—S(═O)₂R^(a), —C(═O)R^(a), or C₁-C₆alkyl.

In some embodiment of a compound of Formula (I), the compound or apharmaceutically acceptable salt, solvate, or stereoisomer thereof is ofFormula (Ia):

wherein:

-   Ring B is heterocycloalkyl;-   each R⁶ is independently oxo, halogen, —CN, —OH, —OR^(a), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(b)R^(c),    —NHS(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), —OC(═O)R^(a),    —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(b)R^(c), —OC(═O)NR^(b)R^(c),    —NR^(b)C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    —C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl),    or —C₁-C₆alkyl(heterocycloalkyl); and-   m is 0-4.

In some embodiment of a compound of Formula (Ia), Ring B is a 4-, 5-,6-, or 7-membered heterocycloalkyl. In some embodiment of a compound ofFormula (Ia), Ring B is a 5-, 6-, or 7-membered heterocycloalkyl. Insome embodiment of a compound of Formula (Ia), Ring B is a 5-memberedheterocycloalkyl. In some embodiment of a compound of Formula (Ia), RingB is a 6-membered heterocycloalkyl. In some embodiment of a compound ofFormula (Ia), Ring B is a 7-membered heterocycloalkyl. In someembodiment of a compound of Formula (Ia),

wherein

-   R^(6′) is hydrogen, —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(b)R^(c),    —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),    —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or    —C₁-C₆alkyl(heterocycloalkyl); and-   p is 0-3.

In some embodiment of a compound of Formula (Ia),

is

In some embodiment of a compound of Formula (Ia),

is

In some embodiment of a compound of Formula (Ia),

is

In some embodiment of a compound of Formula (Ia),

is

In some embodiment of a compound of Formula (Ia),

is

In some embodiment of a compound of Formula (Ia),

is

In some embodiment of a compound of Formula (Ia), m is 0-3. In someembodiment of a compound of Formula (Ia), m is 0-2. In some embodimentof a compound of Formula (Ia), m is 0 or 1. In some embodiment of acompound of Formula (Ia), m is 1 or 2. In some embodiment of a compoundof Formula (Ia), m is 1-3. In some embodiment of a compound of Formula(Ia), m is 0. In some embodiment of a compound of Formula (Ia), m is 1.In some embodiment of a compound of Formula (Ia), m is 2. In someembodiment of a compound of Formula (Ia), m is 3. In some embodiment ofa compound of Formula (Ia), m is 4.

In some embodiment of a compound of Formula (Ia), each R⁶ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),—C(═O)R^(a), —C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiment of a compound of Formula (Ia), eachR⁶ is independently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl;wherein each alkyl is independently optionally substituted with one,two, or three oxo, halogen, —CN, —OH, —OMe, —NH₂, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiment of a compound of Formula (Ia), eachR⁶ is independently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl; wherein each alkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiment of acompound of Formula (Ia), each R⁶ is independently oxo, halogen, —CN,—OH, —OMe, —NH₂, Me, or CF₃. In some embodiment of a compound of Formula(Ia), each R⁶ is independently oxo, halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl. In some embodiment of acompound of Formula (Ia), each R⁶ is independently halogen.

In some embodiment of a compound of Formula (Ia), each R⁶ isindependently halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), —S(═O)₂R^(a),—S(═O)₂NR^(b)R^(c), —C(═O)R^(a), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, or cycloalkyl. In some embodiment of a compound ofFormula (Ia), each R⁶ is independently halogen, —OH, —S(═O)₂R^(a),—C(═O)R^(a), or C₁-C₆alkyl. In some embodiment of a compound of Formula(Ia), each R⁶ is independently halogen, —S(═O)₂R^(a), —C(═O)R^(a), orC₁-C₆alkyl. In some embodiment of a compound of Formula (Ia), each R⁶ isindependently halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or cycloalkyl. In some embodiment ofa compound of Formula (Ia), each R⁶ is independently halogen orC₁-C₆alkyl.

In some embodiment of a compound of Formula (Ia), p is 0-2. In someembodiment of a compound of Formula (Ia), p is 0 or 1. In someembodiment of a compound of Formula (Ia), p is 1 or 2. In someembodiment of a compound of Formula (Ia), p is 1-3. In some embodimentof a compound of Formula (Ia), p is 0. In some embodiment of a compoundof Formula (Ia), p is 1. In some embodiment of a compound of Formula(Ia), p is 2. In some embodiment of a compound of Formula (Ia), p is 3.

In some embodiment of a compound of Formula (Ia), R^(6′) is hydrogen,—S(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —C(═O)R^(a), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or cycloalkyl. In some embodiment ofa compound of Formula (Ia), R^(6′) is hydrogen, —S(═O)₂R^(a),—C(═O)R^(a), or C₁-C₆alkyl. In some embodiment of a compound of Formula(Ia), R^(6′) is hydrogen or C₁-C₆alkyl.

In some embodiment of a compound of Formula (I) or (Ia), the compound ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof isof Formula (Ib):

In some embodiment of a compound of Formula (I) or (Ia), the compound ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof isof Formula (Ic):

In some embodiment of a compound of Formula (I) or (Ia), the compound ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof isof Formula (Id):

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹² ishydrogen or C₁-C₆alkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), R¹² is hydrogen. In some embodiment of a compound of Formula(I), (Ia)-(Id), R¹² is C₁-C₆alkyl.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹³ ishydrogen, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three R³. In some embodiment ofa compound of Formula (I), (Ia)-(Id), R¹³ is hydrogen, halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, orcycloalkyl; wherein each alkyl or cycloalkyl is independently optionallysubstituted with one, two, or three R³. In some embodiment of a compoundof Formula (I), (Ia)-(Id), R¹³ is hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl; wherein each alkyl is independently optionallysubstituted with one, two, or three R³. In some embodiment of a compoundof Formula (I), (Ia)-(Id), R¹³ is hydrogen, halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), —C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl,C₁-C₆haloalkyl, or cycloalkyl. In some embodiment of a compound ofFormula (I), (Ia)-(Id), R¹³ is hydrogen, halogen, or C₁-C₆alkyl. In someembodiment of a compound of Formula (I), (Ia)-(Id), R¹³ is hydrogen orC₁-C₆alkyl. In some embodiment of a compound of Formula (I), (Ia)-(Id),R¹³ is C₁-C₆alkyl.

In some embodiment of a compound of Formula (I), (Ia)-(Id), each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl inR¹³ is optionally substituted with one, two, or three R³. In someembodiment of a compound of Formula (I), (Ia)-(Id), each alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl in R¹³ isoptionally substituted with one or two R³. In some embodiment of acompound of Formula (I), (Ia)-(Id), each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl in R¹³ is optionallysubstituted with one R³. In some embodiment of a compound of Formula(I), (Ia)-(Id), each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl in R¹³ is optionally substitutedwith two R³. In some embodiment of a compound of Formula (I), (Ia)-(Id),each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl in R¹³ is optionally substituted with three R³.

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R³ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),—C(═O)R^(a), —C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R³ is independently oxo, halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl; wherein each alkyl is independently optionallysubstituted with one, two, or three oxo, halogen, —CN, —OH, —OMe, —NH₂,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiment of a compound ofFormula (I), (Ia)-(Id), each R³ is independently oxo, halogen, —CN, —OH,—OR^(a), —NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl; wherein each alkyl isindependently optionally substituted with one, two, or three oxo,halogen, —CN, —OH, —OMe, —NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiment of a compound of Formula (I), (Ia)-(Id), each R³ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl,C₁-C₆haloalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R³ is independently oxo, halogen, —CN, —OH, —OMe, —NH₂,Me, or CF₃. In some embodiment of a compound of Formula (I), (Ia)-(Id),each R³ is independently halogen.

In some embodiment of a compound of Formula (I), (Ia)-(Id), Ring A iscycloalkyl or heterocycloalkyl. In some embodiment of a compound ofFormula (I), (Ia)-(Id), Ring A is cycloalkyl, aryl or heteroaryl. Insome embodiment of a compound of Formula (I), (Ia)-(Id), Ring A is arylor heteroaryl. In some embodiment of a compound of Formula (I),(Ia)-(Id), Ring A is phenyl or 5- or 6-membered heteroaryl. In someembodiment of a compound of Formula (I), (Ia)-(Id), Ring A is phenyl or6-membered heteroaryl. In some embodiment of a compound of Formula (I),(Ia)-(Id), Ring A is phenyl or pyridyl. In some embodiment of a compoundof Formula (I), (Ia)-(Id), Ring A is phenyl.

In some embodiment of a compound of Formula (I), (Ia)-(Id), n is 0-3. Insome embodiment of a compound of Formula (I), (Ia)-(Id), n is 0-2. Insome embodiment of a compound of Formula (I), (Ia)-(Id), n is 0 or 1. Insome embodiment of a compound of Formula (I), (Ia)-(Id), n is 1-3. Insome embodiment of a compound of Formula (I), (Ia)-(Id), n is 1 or 2. Insome embodiment of a compound of Formula (I), (Ia)-(Id), n is 0. In someembodiment of a compound of Formula (I), (Ia)-(Id), n is 1. In someembodiment of a compound of Formula (I), (Ia)-(Id), n is 2. In someembodiment of a compound of Formula (I), (Ia)-(Id), n is 3. In someembodiment of a compound of Formula (I), (Ia)-(Id), n is 4.

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R¹¹ isindependently halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three R¹. In some embodiment ofa compound of Formula (I), (Ia)-(Id), each R¹¹ is independently halogen,—CN, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one, two, or three R¹. In some embodiment ofa compound of Formula (I), (Ia)-(Id), each R¹¹ is independently halogen,—CN, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl;wherein each alkyl is independently optionally substituted with one,two, or three R¹. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R¹¹ is independently halogen, —CN, C₁-C₆alkyl, orC₁-C₆haloalkyl; wherein each alkyl is independently optionallysubstituted with one, two, or three R¹. In some embodiment of a compoundof Formula (I), (Ia)-(Id), each R¹¹ is independently halogen, —CN, —OH,—OR^(a), —NR^(b)R^(c), —C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl,C₁-C₆haloalkyl, or cycloalkyl. In some embodiment of a compound ofFormula (I), (Ia)-(Id), each R¹¹ is independently halogen, —CN,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiment of a compound ofFormula (I), (Ia)-(Id), each R¹¹ is independently halogen or C₁-C₆alkyl.

In some embodiment of a compound of Formula (I), (Ia)-(Id), each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl inR¹¹ is optionally substituted with one, two, or three R¹. In someembodiment of a compound of Formula (I), (Ia)-(Id), each alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl in R¹¹ isoptionally substituted with one or two R¹. In some embodiment of acompound of Formula (I), (Ia)-(Id), each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl in R¹¹ is optionallysubstituted with one R¹. In some embodiment of a compound of Formula(I), (Ia)-(Id), each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl in R₁₁ is optionally substitutedwith two R¹. In some embodiment of a compound of Formula (I), (Ia)-(Id),each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl in R¹¹ is optionally substituted with three R¹.

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R¹ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),—C(═O)R^(a), —C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R¹ is independently oxo, halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl; wherein each alkyl is independently optionallysubstituted with one, two, or three oxo, halogen, —CN, —OH, —OMe, —NH₂,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiment of a compound ofFormula (I), (Ia)-(Id), each R¹ is independently oxo, halogen, —CN, —OH,—OR^(a), —NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl; wherein each alkyl isindependently optionally substituted with one, two, or three oxo,halogen, —CN, —OH, —OMe, —NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiment of a compound of Formula (I), (Ia)-(Id), each R¹ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl,C₁-C₆haloalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R¹ is independently oxo, halogen, —CN, —OH, —OMe, —NH₂,Me, or CF₃. In some embodiment of a compound of Formula (I), (Ia)-(Id),each R¹ is independently halogen.

In some embodiment of a compound of Formula (I), (Ia)-(Id), two R¹¹ onadjacent atoms are taken together with the atoms to which they areattached to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each optionally substituted with one, two, or three R². In someembodiment of a compound of Formula (I), (Ia)-(Id), two R¹¹ on adjacentatoms are taken together with the atoms to which they are attached toform a cycloalkyl optionally substituted with one, two, or three R². Insome embodiment of a compound of Formula (I), (Ia)-(Id), two R¹¹ onadjacent atoms are taken together with the atoms to which they areattached to form a heterocycloalkyl optionally substituted with one,two, or three R². In some embodiment of a compound of Formula (I),(Ia)-(Id), two R¹¹ on adjacent atoms are taken together with the atomsto which they are attached to form an aryl optionally substituted withone, two, or three R². In some embodiment of a compound of Formula (I),(Ia)-(Id), two R¹¹ on adjacent atoms are taken together with the atomsto which they are attached to form a heteroaryl optionally substitutedwith one, two, or three R².

In some embodiment of a compound of Formula (I), (Ia)-(Id), eachcycloalkyl, heterocycloalkyl, aryl, or heteroaryl formed when two R¹¹are taken together is optionally substituted with one, two, or three R².In some embodiment of a compound of Formula (I), (Ia)-(Id), eachcycloalkyl, heterocycloalkyl, aryl, or heteroaryl formed when two R¹¹are taken together is optionally substituted with one or two R². In someembodiment of a compound of Formula (I), (Ia)-(Id), each cycloalkyl,heterocycloalkyl, aryl, or heteroaryl formed when two R¹¹ are takentogether is optionally substituted with one R². In some embodiment of acompound of Formula (I), (Ia)-(Id), each cycloalkyl, heterocycloalkyl,aryl, or heteroaryl formed when two R¹¹ are taken together is optionallysubstituted with two R². In some embodiment of a compound of Formula(I), (Ia)-(Id), R¹¹ is optionally substituted with three R².

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R² isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),—C(═O)R^(a), —C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R² is independently oxo, halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl; wherein each alkyl is independently optionallysubstituted with one, two, or three oxo, halogen, —CN, —OH, —OMe, —NH₂,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiment of a compound ofFormula (I), (Ia)-(Id), each R² is independently oxo, halogen, —CN, —OH,—OR^(a), —NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl; wherein each alkyl isindependently optionally substituted with one, two, or three oxo,halogen, —CN, —OH, —OMe, —NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiment of a compound of Formula (I), (Ia)-(Id), each R² isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl,C₁-C₆haloalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R² is independently oxo, halogen, —CN, —OH, —OMe, —NH₂,Me, or CF₃. In some embodiment of a compound of Formula (I), (Ia)-(Id),each R² is independently halogen.

In some embodiment of a compound of Formula (I), (Ia)-(Id),

is

In some embodiment of a compound of Formula (I), (a)-(Id),

is

In some embodiment of a compound of Formula (I), (Ia)-(Id),

is

In some embodiment of a compound of Formula (I), (Ia)-(Id),

is

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁶ ishydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one, two, or three R⁷. In some embodiment of a compound of Formula(I), (Ia)-(Id), R¹⁶ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl; wherein each alkyl isindependently optionally substituted with one, two, or three R⁷. In someembodiment of a compound of Formula (I), (Ia)-(Id), R¹⁶ is hydrogen,C₁-C₆alkyl, or C₁-C₆haloalkyl; wherein each alkyl is independentlyoptionally substituted with one, two, or three R⁷. In some embodiment ofa compound of Formula (I), (Ia)-(Id), R¹⁶ is hydrogen or C₁-C₆alkyl. Insome embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁶ ishydrogen.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ ishydrogen, —CN, —OR²⁰, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₅cycloalkyl,C₂-C₁₅heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl,—C₁-C₆alkyl(phenyl), —C₁-C₆alkyl(5- or 6-membered heteroaryl),—C₁-C₆alkyl(C₃-C₁₅cycloalkyl), or —C₁-C₆alkyl(C₂-C₁₅heterocycloalkyl);wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, and heteroaryl is independently optionally substituted with one,two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ ishydrogen, —CN, —OR²⁰, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl,C₂-C₁₀heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl,—C₁-C₆alkyl(phenyl), —C₁-C₆alkyl(5- or 6-membered heteroaryl),—C₁-C₆alkyl(C₃-C₁₀cycloalkyl), or —C₁-C₆alkyl(C₂-C₁₀heterocycloalkyl);wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, and heteroaryl is independently optionally substituted with one,two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ is—OR²⁰, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₂-C₁₀cycloalkenyl,C₃-C₁₀heterocycloalkyl, C₂-C₁₀heterocycloalkenyl, phenyl, 5- or6-membered heteroaryl, —C₁-C₆alkyl(phenyl), —C₁-C₆alkyl(5- or 6-memberedheteroaryl), —C₁-C₆alkyl(C₃-C₁₀cycloalkyl), or—C₁-C₆alkyl(C₂-C₁₀heterocycloalkyl); wherein each alkyl, alkynyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ is—OR²⁰, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl,C₂-C₁₀heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl,—C₁-C₆alkyl(5- or 6-membered heteroaryl), —C₁-C₆alkyl(C₃-C₁₀cycloalkyl),or —C₁-C₆alkyl(C₂-C₁₀heterocycloalkyl); wherein each alkyl, alkynyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ is—OR²⁰, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₂-C₆alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),—C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or—C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkynyl, cycloalkyl,cycloalkeny, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroarylis independently optionally substituted with one, two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ is—OR²⁰, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₂-C₆alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or—C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ is—OR²⁰, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,—C₁-C₆alkyl(aryl), —C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or—C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ is—OR²⁰, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,cycloalkyl, heterocycloalkyl, —C₁-C₆alkyl(aryl),—C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or—C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ is—OR²⁰, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, cycloalkyl,heterocycloalkyl, —C₁-C₆alkyl(heteroaryl), or —C₁-C₆alkyl(cycloalkyl);wherein each alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl isindependently optionally substituted with one, two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ isC₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or cycloalkyl; eachoptionally substituted with one, two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ isC₁-C₆hydroxyalkyl, cycloalkyl, or heterocycloalkyl; each optionallysubstituted with one, two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ isC₁-C₆alkyl or cycloalkyl; each optionally substituted with one, two, orthree R⁷. In some embodiment of a compound of Formula (I), (Ia)-(Id),R¹⁷ is C₁-C₆alkyl optionally substituted with one, two, or three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁷ isC₁-C₆haloalkyl, C₁-C₆hydroxyalkyl or cycloalkyl; each optionallysubstituted with one, two, or three R⁷. In some embodiment of a compoundof Formula (I), (Ia)-(Id), R¹⁷ is C₁-C₆haloalkyl optionally substitutedwith one, two, or three R⁷. In some embodiment of a compound of Formula(I), (Ia)-(Id), R¹⁷ is C₁-C₆hydroxyalkyl optionally substituted withone, two, or three R⁷. In some embodiment of a compound of Formula (I),(Ia)-(Id), R¹⁷ is cycloalkyl optionally substituted with one, two, orthree R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), each alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, or heteroaryl in R¹⁶ or R¹⁷ is optionallysubstituted with one, two, or three R⁷. In some embodiment of a compoundof Formula (I), (Ia)-(Id), each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroarylin R¹⁶ or R¹⁷ is optionally substituted with one or two R⁷. In someembodiment of a compound of Formula (I), (Ia)-(Id), each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,aryl, or heteroaryl in R¹⁶ or R¹⁷ is optionally substituted with one R⁷.In some embodiment of a compound of Formula (I), (Ia)-(Id), each alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, or heteroaryl in R¹⁶ or R¹⁷ is optionallysubstituted with two R⁷. In some embodiment of a compound of Formula(I), (Ia)-(Id), each each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroarylin R¹⁶ or R¹⁷ is optionally substituted with three R⁷.

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R⁷ isindependently oxo, halogen, —CN, —OH, —OR^(a), —S(═O)₂R^(a),—NR^(b)R^(c), —NHS(═O)₂R^(a), —S(═O)₂NR^(b)R^(c), —B(OR^(b))(OR^(c)),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(7a).

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R⁷ isindependently oxo, halogen, —CN, —OH, —OR^(a), —S(═O)₂R^(a),—NR^(b)R^(c), —NHS(═O)₂R^(a), —B(OR^(b))(OR^(c)), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(b)R^(c), —NR^(b)C(═O)R^(a), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, cycloalkyl, heterocycloalkyl, orheteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(7a).

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R⁷ isindependently halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),—B(OR^(b))(OR^(c)), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(b)R^(c),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(7a).

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R⁷ isindependently halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one, two, or three R^(7a).

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R⁷ isindependently halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), —C(═O)OR^(b),—C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,cycloalkyl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, and heteroaryl is independently optionally substitutedwith one, two, or three R^(7a). In some embodiment of a compound ofFormula (I), (Ia)-(Id), each R⁷ is independently halogen, —OH, —OR^(a),—C(═O)OR^(b), —C(═O)NR^(b)R^(c), C₁-C₆alkyl, or heteroaryl; wherein eachalkyl, cycloalkyl and heteroaryl is independently optionally substitutedwith one, two, or three R^(7a). In some embodiment of a compound ofFormula (I), (Ia)-(Id), each R⁷ is independently halogen, —C(═O)OR^(b),—C(═O)NR^(b)R^(c), C₁-C₆alkyl, or heteroaryl; wherein each alkyl,cycloalkyl and heteroaryl is independently optionally substituted withone, two, or three R^(7a). In some embodiment of a compound of Formula(I), (Ia)-(Id), each R⁷ is independently halogen, —C(═O)OR^(b),—C(═O)NR^(b)R^(c), or heteroaryl optionally substituted with one, two,or three R^(7a). In some embodiment of a compound of Formula (I),(Ia)-(Id), each R⁷ is independently halogen, —C(═O)OR^(b), or—C(═O)NR^(b)R^(c). In some embodiment of a compound of Formula (I),(Ia)-(Id), each R⁷ is independently —C(═O)OR^(b) or —C(═O)NR^(b)R^(c).

In some embodiment of a compound of Formula (I), (Ia)-(Id), each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl inR⁷ is optionally substituted with one, two, or three R^(7a). In someembodiment of a compound of Formula (I), (Ia)-(Id), each alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl in R⁷ isoptionally substituted with one or two R^(7a). In some embodiment of acompound of Formula (I), (Ia)-(Id), each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl in R⁷ is optionallysubstituted with one R^(7a). In some embodiment of a compound of Formula(I), (Ia)-(Id), each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl in R⁷ is optionally substitutedwith two R^(7a). In some embodiment of a compound of Formula (I),(Ia)-(Id), each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl in R⁷ is optionally substituted with three R^(7a).

In some embodiments, when R⁷ is —B(OR^(b))(OR^(c)); one of the oxygen onthe boron can form a cyclic structure with one of the carbonyl group:

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R^(7a)is independently halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl,or C₁-C₆haloalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R^(7a) is independently oxo, halogen, —CN, —OH, —OMe,—NH₂, Me, or CF₃. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R^(7a) is independently halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R^(7a) is independently halogen.

In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁶ and R¹⁷are taken together with the nitrogen atom to which they are attached toform a heterocycloalkyl optionally substituted with one, two, or threeR⁸. In some embodiment of a compound of Formula (I), (Ia)-(Id), R¹⁶ andR¹⁷ are taken together with the nitrogen atom to which they are attachedto form a heterocycloalkyl optionally substituted with one, two, orthree R⁸; wherein the heterocycloalkyl is pyrrolidine, piperidine,morpholine, or piperazine. In some embodiment of a compound of Formula(I), (Ia)-(Id), R¹⁶ and R¹⁷ are taken together with the nitrogen atom towhich they are attached to form a heterocycloalkyl optionallysubstituted with one, two, or three R⁸; wherein the heterocycloalkyl ispiperidine.

In some embodiment of a compound of Formula (I), (Ia)-(Id), theheterocycloalkyl or heterocycloalkenyl formed when R¹⁶ and R¹⁷ are takentogether is optionally substituted with one, two, or three R⁸. In someembodiment of a compound of Formula (I), (Ia)-(Id), the heterocycloalkylor heterocycloalkenyl formed when R¹⁶ and R¹⁷ are taken together isoptionally substituted with one or two R⁸. In some embodiment of acompound of Formula (I), (Ia)-(Id), the heterocycloalkyl orheterocycloalkenyl formed when R¹⁶ and R¹⁷ are taken together isoptionally substituted with one R⁸. In some embodiment of a compound ofFormula (I), (Ia)-(Id), the heterocycloalkyl or heterocycloalkenylformed when R¹⁶ and R¹⁷ are taken together is optionally substitutedwith two R⁸. In some embodiment of a compound of Formula (I), (Ia)-(Id),the heterocycloalkyl or heterocycloalkenyl formed when R¹⁶ and R¹⁷ aretaken together is optionally substituted with three R⁸.

In some embodiment of a compound of Formula (I), (Ia)-(Id), each R⁸ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c),—C(═O)R^(a), —C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three oxo, halogen, —CN, —OH,—OMe, —NH₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R⁸ is independently oxo, halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl; wherein each alkyl is independently optionallysubstituted with one, two, or three oxo, halogen, —CN, —OH, —OMe, —NH₂,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiment of a compound ofFormula (I), (Ia)-(Id), each R⁸ is independently oxo, halogen, —CN, —OH,—OR^(a), —NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl; wherein each alkyl isindependently optionally substituted with one, two, or three oxo,halogen, —CN, —OH, —OMe, —NH₂, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiment of a compound of Formula (I), (Ia)-(Id), each R⁸ isindependently oxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl,C₁-C₆haloalkyl. In some embodiment of a compound of Formula (I),(Ia)-(Id), each R⁸ is independently halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆hydroxyalkyl. In someembodiment of a compound of Formula (I), (Ia)-(Id), each R⁸ isindependently oxo, halogen, —CN, —OH, —OMe, —NH₂, Me, or CF₃. In someembodiment of a compound of Formula (I), (Ia)-(Id), each R⁸ isindependently —OH or C₁-C₆alkyl. In some embodiment of a compound ofFormula (I), (Ia)-(Id), each R⁸ is independently oxo, halogen, —CN, —OH,—OR^(a), —NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆hydroxyalkyl.

In some embodiment of a compound of Formula (I), (Ia)-(Id),

is

In some embodiment of a compound of Formula (I), (Ia)-(Id),

is

In some embodiment of a compound of Formula (I), (Ia)-(Id),

is

In some embodiments of a compound of Formula (I), (Ia)-(Id), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Insome embodiments of a compound of Formula (I), (Ia)-(Id), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, orheterocycloalkyl. In some embodiments of a compound of Formula (I),(Ia)-(Id), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R¹¹ is independently C₁-C₆alkyl,C₁-C₆haloalkyl, or cycloalkyl. In some embodiments of a compound ofFormula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, each R^(a) is independently C₁-C₆alkyl orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (I),(Ia)-(Id), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(a) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (I), (Ia)-(Id), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(b) and R^(c) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl. In some embodiments of a compound of Formula (I),(Ia)-(Id), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(b) and R^(c) is independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl. In someembodiments of a compound of Formula (I), (Ia)-(Id), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(b) and R^(c) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,or cycloalkyl. In some embodiments of a compound of Formula (I),(Ia)-(Id), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(b) and R^(c) is independently hydrogen,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, each R^(b) and R^(c) is independently hydrogenor C₁-C₆alkyl. In some embodiments of a compound of Formula (I),(Ia)-(Id), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(b) and R^(c) is hydrogen.

In some embodiments of a compound of Formula (I), (Ia)-(Id), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(b) and R^(c) are taken together with the atom to which they areattached to form a heterocycloalkyl optionally substituted with one,two, or three halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

Described herein is a compound of Formula (I), (Ia)-(Id), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,selected from a compound in Table 1.

TABLE 1 Exemplary compounds ESI-MS (M + H)⁺ Ex. Structure Chemical Name(m/z) 1

5-(2-(tert-butylamino)-2- oxocetyl)-N-(4-fluoro-3-methylphenyl)-1-methyl-1H- pyrrole-3-carboxamide 360.1 2

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 388.2 3

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(3-chloro-4-fluorophenyl)-2,4-dimethyl- 1H-pyrrole-3-carboxamide 394 4

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(3,4- difluorophenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 392.2 5

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(2-fluoropyridin-4-yl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 375.2 6

5-(2-((1-fluoro-2- methylpropan-2-yl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 428.2 7

N-(4-fluoro-3-methylphenyl)- 5-(2-((1- (hydroxymethyl)cyclopropyl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 402.2 8

N-(4-fluoro-3-methylphenyl)- 5-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 404.2 9

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoro-2- methylpropan-2- yl)amino)acetyl)-1H-pyrrole-3-carboxamide 442.2 10

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide428.2 11

N-(4-fluoro-3-methylphenyl)- 5-(2-((4-hydroxy-2-methylbutan-2-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 418.2 12

N-(4-fluoro-3-methylphenyl)- 5-(2-((1- (hydroxymethyl))cyclobutyl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 416.2 13

N-(4-fluoro-3-methylphenyl)- 5-(2-((3- (hydroxymethyl)tetrahydrofuran-3-yl)amino)-2-oxoacetyl)- 1,2,4-trimethyl-1H-pyrrole-3- carboxamide432.2 14

5-(2-(((3s,5s,7s)-adamantan-1- yl)amino)-2-oxocetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 466.215

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1r,3s,5R,7S)-3- hydroxyadamantan-1-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 482.216

N-(2-fluoropyridin-4-yl)-5-(2- (((1r,3s,5R,7S)-3- hydroxyadamantan-1-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 469.217

5-(2-(((1r,3r)-adamantan-2- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 466.118

N-(4-fluoro-3-methylphenyl)- 5-(2-(((2R,3a,5S,6as)- hexahydro-2,5-methanopentalen-3a(1H)- yl)amino)-2-oxoacetyl)-1,2,4-trimetnyl-1H-pyrrole-3- carboxamide 452.2 19

N-(2-fluoropyridin-4-yl)-5-(2- (((2R,3s,5S,6as)-hexahydro-2,5-methanopentalen-3a(1H)- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 439.2 20

5-(2-((2-amino-4,5,6,7- tetrahydrobenzo[d]thiazol-6-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 484.1 21

5-(2-(tert-butoxyamino)-2- oxoacetyl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H- pyrrole-3-carboxamide 396 22

tert-butyl 2-(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)-2- methylpropanoate474.2 23

tert-butyl (S)-2-(2-(4-((4- fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)-3,3- dimethylbutanoate502.2 24

methyl (R)-2-(2-(4-((4-fluoro- 3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)-3,3- dimethylbutanoate460.2 25

ethyl (2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-L-serinate 448.2 26

ethyl (2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-D-serinate 448.2 27

methyl (2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-L-threoninate 448.2 28

methyl (2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-D-threoninate 448.2 29

2-(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)-2- methylpropanoic acid418.2 30

(S)-2-(22-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)-3,3- dimethylbutanoicacid 446.2 31

(R)-2-(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)-3,3- dimethylbutanoicacid 446.2 32

(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-L-serine 420.2 33

(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-D-serine 420.2 34

(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-L-threonine 434.2 35

(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-D-threonine 434.2 36

5-(2-((1-amino-2-methyl-1- oxopropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 439.2 37

5-(2-((1- carbamoylcyclopropyl)amino)- 2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 415.2 38

5-(2-((1- carbamoylcyclopentyl)amino)- 2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 443.2 39

(S)-5-(2-((1-amino-3,3- dimethyl-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 445.2 40

(R)-5-(2-((1-amino-3,3- dimethyl-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 445.2 41

(S)-5-(2-((1-amino-3-hydroxy- 1-oxopropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 419.2 42

5-(2-(((2S,3R)-1-amino-3- hyrdroxy-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- caarboxamide 433.2 43

5-(2-(((1r,3r,5r,7r)-2- carbamoyladamantan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 509.2 44

5-(2-(((2R,3S)-1-amino-3- hydroxy-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 433.2 45

methyl (2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-L- allothreoninate 448.246

methyl (2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-D- allothreoninate 448.247

N-(4-fluoro-3-methylphenyl)- 5-(2-(4-hydroxypiperidin-1-yl)-2-oxoacetyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 416.2 48

N-(4-fluoro-3-methylphenyl)- 5-(2-((1R,3s,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 442.2 49

5-(2-(2-amino-6,7- dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 470.1 50

N-(4-fluoro-3-methylphenyl)- 5-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-1-(2-hydroxyethyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide 434.2 51

(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-L- allothreonine 434.2 52

(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-D- allothreonine 434.2 53

N-(4-fluoro-3-methylphenyl)- 5-(2-(4-hydroxy-3,3-dimethylpiperidin-1-yl)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 444.2 54

(R)-5-(2-((1-amino-3-hydroxy- 1-oxopropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 419.2 55

methyl (S)-2-cyclohexyl-2-(2- (4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)acetate 486.2 56

methyl (R)-2-cyclohexyl-2-(2- (4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)acetate 486.2 57

5-(2-(((2S,3S)-1-amino-3- hydroxy-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 433.2 58

N-(4-fluoro-3-methylphenyl)- 5-(2-(((2S,3S)-3-hydorxy-1-(methylamino)-1-oxobutan-2- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 447.2 59

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1s,3r,4s,5S,7s)-4-hydroxyadamantan-1- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 482.2 60

(R)-5-(2-((3,3-dimethyl-1- (methylamino)-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 459.2 61

5-(2-(((2R,3R)-1-amino-3- hydroxy-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 433.2 62

N-(4-fluoro-3-methylphenyl)- 5-(2-(((2R,3R)-3-hydroxy-1-(methylmaino)-1-oxobutan-2- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 447.2 63

(R)-5-(2-((3,3-dimethylbutan- 2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 416.264

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2- (neopentylamino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 402.2 65

N-(4-fluoro-3-methylphenyl)- 5-(2-((3-hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 418.2 66

N-(4-fluoro-3-methylphenyl)- 5-(2-((2-hydroxy-2- methylethyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 404.2 67

(S)-N-(4-fluoro-3- methylphenyl)-5-(2-((1- hydroxy-3,3-dimethylbutan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 432.268

(S)-2-cyclohexyl-2-(2-(4-((4- fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)acetic acid 472.2 69

(R)-2-cyclohexyl-2-(2-(4-((4- fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)acetic acid 472.2 70

5-(2-(tert-butoxyamino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 404 71

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1-(2-hydroxyethyl)-2,4-dimethyl- 1H-pyrrole-3-carboxamide 418.2 72

5-(2-((1-amino-2-methyl-1- oxopropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1-(2-hydroxyethyl)-2,4-dimethyl- 1H-pyrrole-3-carboxamide 447.2 73

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1r,3s,5R,7S)-3- hydroxyadamantan-1-yl)amino)-2-oxoacetyl)-1-(2- hydroxyethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 512.2 74

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1R,2s,3S,5s,7s)-5-hydroxyadamantan-2- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 482.2 75

(S)-5-(2-((2-amino-4,5,6,7- tetrahydrobenzo[d]thiazol-6-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 484.2 76

(R)-5-(2-((2-amino-4,5,6,7- tetrahydrobenzo[d]thiazol-6-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 484.2 77

5-(2-((2-amino-4,5,6,7- tetrahydrobenzo[d]thiazol-6-yl)amino)-2-oxoacetyl)-N-(6- fluoropyridin-3-yl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 471.1 78

(R)-N-(4-fluoro-3- methylphenyl)-5-(2-((1- hydroxy-3,3-dimethylbutan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 432.279

5-(2-((1-(2H-tetrazol-5- yl)ethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-1H-pyrrole-3- carboxamide428 80

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((3-methyl-1-(2H-tetrazol-5- yl)butyl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 470 81

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2-methyl-1-(3-methyl-1,2,4- oxoadiazol-5-yl)-propyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 470 82

5-(2-((cyclopropyl(5- methylthiazol-2- yl)methyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 442.2 83

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2-(5-methylthiazol-2-yl)propan-2- ylamino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 483 84

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-(((3-methyl-1,2,4-oxadiazol-5- yl)tetrahydro-2H-pyran-4- yl)methyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 471 85

5-(2-((cyclopropyl(5- methylthiazol-2- yl)methyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 512 86

(R)-N-(4-fluoro-3- methylphenyl)-5-(2-((1-((2- hydroxyethyl)amino)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoacteyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 490 87

(R)-N-(4-fluoro-3- methylphenyl)-5-(2-((1-((2- hydroxy-2-methylpropyl)amino)-3,3- dimethyl-1-oxobutan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 518 88

(S)-5-(2-((3,3-dimethylbutan- 2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 417 89

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(2-fluoropyridin-4-yl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 375.2 90

N-(2-fluoropyridin-4-yl)-5-(2- (((2R,3as,5S,6as)-hexahydro-2,5-methanopentalen-3a(1H)- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 439.2 91

5-(2-(((1r,3r)-adamantan-2- yl)amino)-2-oxoacetyl)-N-(6-fluoropyridin-3-yl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 453.2 92

N-(6-fluoropyridin-3-yl)-5-(2- (((1R,2s,3S,5s,7s)-5- hydroxyadamantan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 469.193

5-(2-((1- carbamoylcyclohexyl)amino)- 2-oxoacetyl)-N-(6-fluoropyridin-3-yl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 444.2 94

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1S,2R)-2-hydroxycyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 416.2 95

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1R,2R)-2-hydroxycyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 416.2 96

5-(2-(tert-butylamino)-2- oxoacetyl)-1-ethyl-N-(4-fluoro-3-methylphenyl)-2,4-dimethyl- 1H-pyrrole-3-carboxamide 402.2 97

5-(2-(((2-aminothiazol-5- yl)methyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 444.1 98

1-ethyl-N-(4-fluoro-3- methylphenyl)-5-(2-((1- hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-2,4- dimethyl-1H-pyrrole-3- carboxamide 418.2 99

5-(2-((1-amino-2-methyl-1- oxopropan-2-yl)amino)-2-oxoacetyl)-1-ethyl-N-(4-fluoro- 3-methylphenyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 431.2 100

(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-L-valine 432 101

(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetyl)-D-valine 432 102

(R)-5-(2-((2-amino-1- cyclohexyl-2-oxoethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 472 103

5-(2-(((2S,3S)-1,3- dihydroxybutan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 420 104

5-(2-((3,3-difluoro-1- (methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 479 105

(R)-5-(2-((1-amino-3-methyl- 1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 431 106

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl- 5-(2-((3-methyl-1-(methylamino)-1-oxobutan-2- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 446 107

(S)-5-(2-((1-amino-3-methyl-1- oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 431 108

(S)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl- 5-(2-((3-methyl-1-(methylamino)-1-oxobutan-2- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 446 109

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((4-(trifluoromethyl)tetrahydro- 2H-pyran-4-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 484.1 110

N-(6-fluoropyridin-3-yl)-1,2,4- trimethyl-5-(2-oxo-2-((4-(trifluoromethyl)tetrahydro- 2H-pyran-4-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 471.1 111

5-(2-(((2-aminothiazol-4- yl)methyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 444.1 112

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(6-fluoro-5-methylpyridin-3-yl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 389.2 113

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((2R,3as,5S,6as)-hexahydro-2,5- methanopentalen-3a(1H)- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 453.2 114

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1r,3s,5R,7S)-3-hydroxyadamantan-1- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 483.2 115

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1-(2-fluoroethyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide 420.2 116

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide 436.2 117

5-(2-((1-amino-2-methyl-1- oxopropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1-(2-fluoroethyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide 449.2 118

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2-(((1R,2s,3S,5s,7s)-5- hydroxyadamantan-2- yl)amino)-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide 514.1 119

N-(6-fluoropyridin-3-yl)-1,2,4- trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide 415.1 120

N-(6-fluoropyridin-3-yl)-5-(2- ((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimtehyl-1H-pyrrole-3- carboxamide 391.1121

N-(6-fluoropyridin-3-yl)-1,2,4- trimethyl-5-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide429.1 122

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1R,2s,3S,5s,7s)-5-hydroxyadamantan-2- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 483.1 123

(S)-5-(2-((1-cyclopropyl-2- (methylamino)-2-oxoethyl)amino)-2-oxoacetyl)- N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 443 124

(S)-5-(2-((1-cyclobutyl-2- (methylamino)-2-oxoethyl)amino)-2-oxoacetyl)- N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 458 125

(S)-5-(2-((1-cyclopentyl-2- (methylamino)-2-oxoethyl)amino)-2-oxoacetyl)- N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 472 126

5-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro- 3-methylpheenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 452 127

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1R,3R)-3-hydroxycyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 416.1 128

N-(4-fluoro-3-methylphenyl)- 5-(2-(((3S,4R)-4- hydroxytetrahydrofuran-3-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 418.1129

N-(4-fluoro-3-methylphenyl)- 5-(22-(((1r,3r)-3-hydroxycyclobutyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 402.1 130

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2- (((3S,4R)-4-hydroxytetrahydrofuran-3- yl)amino)-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide 450.1 131

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1S,2S)-2-hydroxycyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 417.1 132

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1R,2R)-2-hydroxycyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 417.1 133

N-(2-fluoropyridin-4-yl)-5-(2- ((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 391.1134

N-(2-fluoropyridin-4-yl)-5-(2- (((1S,2S)-2- hydroxycyclopentyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 403.1 135

N-(5-fluoropyridin-2-yl)-5-(2- (((2R,3as,5S,6as)-hexahydro-2,5-methanopentalen-3a(1H)- l)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 439.2 136

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 430.1 137

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1s,4s)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 430.1 138

(S)-5-(2-((2-amino-4,5,6,7- tetrahydrobenzo[d]thiazol-6-yl)amino)-2-oxoacetyl)-N-(6- fluoro-5-methylpyridin-3-yl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 485.1 139

(S)-N-(4-fluoro-3- methylphenyl)-5-(2-((1- hydroxybutan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 404 140

(R)-N-(4-fluoro-3- methylphenyl)-5-(2-((1- hydroxybutan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 404 141

(R)-N-(4-fluoro-3- methylphenyl)-5-(2-((4- hydroxybutan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 404 142

(S)-N-(4-fluoro-3- methylphenyl)-5-(2-((4- hydroxybutan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 404 143

5-(2-(((2R,3R)-1,3- dihydroxybutan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 420 144

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-5-(2-((2-methyl-1-(3-methyl- 1,2,4-oxadiazol-5-yl)propyl)amino)-2-oxoacetyl)- 1H-pyrrole-3-carboxamide 471 145

(S)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-5-(2-((2-methyl-1-(3-methyl- 1,2,4-oxadiazol-5-yl)propyl)amino)-2-oxoacetyl)- 1H-pyrrole-3-carboxamide 471 146

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1R,2S)-2-hydroxxycyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 416.1 147

5-(2-((1- carbamoylcyclopentyl)amino)- 2-oxoacetyl)-N-(3,4-difluorophenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 447.2 148

N-(3,4-difluorophenyl)-5-(2- ((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 408.2149

N-(4-fluoro-3-methylphenyl)- 5-(2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran- 4-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 432.1 150

N-(4-fluoro-3-methylphenyl)- 5-(2-(((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)amino)- 2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 446.1 151

5-(2-(((1R,2S,3S)-2,3- dihydroxycyclopentyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 432.1 152

5-(2-(((1R,2R,3S)-2,3- dihydroxycyclopentyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 432.1 153

5-(2-((1-(5-(difluoromethyl)- 1,2,4-oxadiazol-3- yl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 504 154

5-(2-((2-(5- ((dimethylamino)methyl)- 1,2,4-oxadiazol-3-yl)propan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 500 155

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-(3-methyl-1,2,4-oxxadiazol-5- yl)cyclopropyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 454 156

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1-hydroxy-2- methylpropan-2-yl)oxy)amino)-2-oxoacetyl)- 1,2,4-trimethyl-1H-pyrrole-3- carboxamide420 157

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2- ((2,2,2-trifluoroethoxy)amino)acetyl)- 1H-pyrrole-3-carboxamide 430 158

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-(5-methyl-1,2,4-oxadiazol-3- yl)cyclopentyl)amino)-2-oxoacetyl)-1H-pyrrole--3 carboxamide 483 159

5-(2-((1-(5-(difluoromethyl)- 1,2,4-oxadiazol-3- yl)cyclobutyl)amino)-2-oxoacetyl)-N-(6-fluoro-5- methylpyridin-3-yl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 505 160

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)cyclopropyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 455 161

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 405.2 162

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 431.3 163

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-oxo-2-((4-(trifluoromethyl)tetrahydro- 2H-pyran-4-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 485.2 164

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran- 4-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 433.2 165

(R)-N-(6-fluoro-5- methylpyridin-3-yl)-1,2,4-trimethyl-5-(2-oxo-2-((1,1,1- trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3- carboxamide 429.1 166

(R)-N-(6-fluoropyridin-3-yl)- 1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide415.1 167

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-((1-methyoxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 419.1 168

N-(6-fluoropyridin-3-yl)-5-(2- ((1-methoxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)- 1,2,4-trimethyl-1H-pyrrole-3- carboxamide405.1 169

N-(4-fluoro-3-methylphenyl)- 5-(2-((1-methoxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 418.2 170

(R)-N-(2-fluoropyridin-4-yl)- 1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide415.1 171

5-(2-(((2-aminothiazol-5- yl)methyl)maino)-2- oxoacetyl)-N-(6-fluoro-5-methylpyridin-3-yl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 445.1 172

N-(2-fluoropyridin-4-yl)-1,2,4- trimethyl-5-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide429.1 173

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoro-2- methylpropan-2- yl)amino)acetyl)-1H-pyrrole-3-carboxamide 443.1 174

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1s,4s)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 431.1 175

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1r,4r)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 431.1 176

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1R,3R)-3-hydroxycyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 417.1 177

5-(2-(((2R,3R)-1,3- dihydroxybutan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1-(2-fluoroethyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide 452 178

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide436 179

5-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro- 33-methylphenyl)-1-(2-fluoroethyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide 484 180

(S)-N-(4-fluoro-3- methylphenyl)-1(2- fluoroethyl)-5-(2-((1-hydroxybutan-2-yl)amino)-2- oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 436 181

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-(5-methyl-1,3,4-oxadiazol-2- yl)ethyl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 442 182

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-(5-methyl-1,3,4-oxadiazol-2- yl)cyclopropyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 454 183

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 405 184

5-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(6-fluoro- 5-methylpyridin-3-yl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 453 185

5-(2-(((2R,3R)-1,3- dihydroxybutan-2-yl)amino)-2-oxoacetyl)-N-(6-fluoro-5- methylpyridin-3-yl)-1,2,4-trimethyl-1H-pyrrole--3 carboxamide 421 186

(S)-N-(6-fluoro-5- methylpyridin-3-yl)-5-(2-((1-hydroxybutan-2-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 405 187

N-(4-fluoro-3-methylphenyl)- 5-(2-(((3R,4S)-3-hydroxytetrahydro-2H-pyran- 4-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 432.2 188

N-(2-fluoropyridin-4-yl)-5-(2- (((1r,3s,5R,7S)-3- hydroxyadamantan-1-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 469.2189

N-(3-chloro-4-fluorophenyl)-5- (2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 424.1 190

N-(2-chloropyridin-4-yl)-5-(2- ((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 407.1191

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-oxo-2-((tetrahydro-2H-thiopyran-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide433.1 192

5-(2-(3,3-difluoropyrrolidin-1- yl)-2-oxoacetyl)-N-(6-fluoro-5-methylpyridin-3-yl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 423.1 193

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-oxo-2- (3-oxo-9-azabicyclo[3.3.1]nonan-9- yl)acetyl)-1H-pyrrole-3- carboxamide 455.1 194

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2- (((1S,3S)-3-hydroxycyclopentyl)amino)-2- oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 448.2 195

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2- (((1R,2R)-2-hydroxycyclopentyl)amino)-2- oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 448.2 196

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2- (((3S,4R)-3-hydroxytetrahydro-2H-pyran- 4-yl)amino)-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide 464.1 197

5-(2-(((1R,2R,3R)-2,4- dihydroxycyclopentyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1-(2-fluoroethyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide 464.2 198

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2-(((1r,4r)-4-hydroxycyclohexyl)amino)- 2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 462.2 199

N-(4-fluoro-3-methylphenyl)- 5-(2-(((2R,3R)-3-hydroxybutan-2-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 404 200

5-(2-((2-(5- ((dimethylamino)methyyl)- 1,2,4-oxadiazol-3-yl)propan-2-yl)amino)-2-oxoacetyl)-N-(6- fluoro-5-methylpyridin-3-yl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 501 201

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-2,4-dimethyl-5-(2-((1-(5-methyl-1,3,4- oxadiazol-2- yl)cyclopropyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 486 202

5-(2-((2-(3- ((dimethylamino)methyl)- 1,2,4-oxadiazol-5-yl)propan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1-(2-fluoroethyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide 532 203

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-2,4-dimethyl-5-(2-((1-(3-methyl-1,2,4- oxadiazol-5- yl)cyclopropyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 486 204

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-(pyridin-3-ylamino)acetyl)-1H- pyrrole-3-carboxamide 409 205

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl) amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 499.2 206

5-(2-((3,3-difluoro-1- methylcyclobutyl)amino)-2-oxoacetyl)-N-(6-fluoro-5- methylpyridin-3-yl)-1,2,4-trimethyl-1H-pyrrole-3-c carboxamide 437.1 207

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl) amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 498.2 208

(R)-N-(2-chloropyridin-4-yl)- 1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide431.1 209

N-(2-chloropyridin-4-yl)-5-(2- (((1R,2s,3S,5s,7s)-5- hydroxyadamantan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 485.1210

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2- (((1s,4s)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 462.1 211

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methylthiazol-2-yl)amino)-2- oxoacetyl)-1H-pyrrole-3- carboxamide 429212

N-(4-fluoro-3-methylphenyl)- 5-(2-((6-fluoropyridin-3-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 427213

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 444.2 214

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 445 215

(S)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-5-(2-((1-(3-methyl-1,2,4- oxadiazol-5-yl)ethyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 442 216

N-(4-fluoro-3-methylphenyl)- 5-(2-((4-fluoro-3- methylphenyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 440 217

(S)-N-(4-ffluoro-3- methylphenyl)-5-(2-((1- hydroxypropan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 390 218

(S)-N-(4-fluoro-3- methylphenyl)-5-(2-((2- hydroxypropyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 390 219

(R)-N-(4-fluoro-3- methylphenyl)-5-(2-((1- hydroxypropan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 390 220

(R)-N-(4-ffluoro-3- methylphenyl)-5-(2-((2- hydroxypropyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 390 221

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl) amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 498.2 222

N-(6-fluoro-5-methylpyridin-3- yl)-1-(2-fluoroethyl)-5-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide 437.2 223

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((tetrahydro-2H-thiopyran-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide432.1 224

N-(6-ffluoro-5-methylpyridin-3- yl)-1-(2-fluoroethyl)-2,4-dimethyl-5-(2-oxo-2-((1,1,1- trifluoro-2-methylpropan-2-yl)amino)acetyl)-1H-pyrrole-3- carboxamide 475.2 225

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(6-fluoro-5-methylpyridin-3-yl)-1-(2- fluoroethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 421.2 226

N-(6-fluoro-5-methylpyridin-3- yl)-1-(2-fluoroethyl)-5-(2-((1-methoxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide 451.3 227

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoro-2- methylpropan-2-yl)amino)acetyl)-1H-pyrrole-3- carboxamide 474.2 228

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1s,4s)-4-hydroxy-1-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 444.2 229

5-(2-(((2-aminothiazol-4- yl)methyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1-(2- fluoroethyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide476.2 230

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)--2,4-dimethyl-5-(2-oxo-2-((4- (trifluoromethyl)tetrahydro-2H-pyran-4-yl)amino)acetyl)- 1H-pyrrole-3-carboxamide 516.1 231

5-(2-((3,4- difluorophenyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 444 232

5-(2-(((1r,4r)-4- aminocyclohexyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 430 233

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-(piperidin-4-ylamino)acetyl)- 1H-pyrrole-3-carboxamide 415 234

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-oxo-2- ((1-(trifluoromethyl)cyclopropyl) amino)acetyl)-1H-pyrrole-3- carboxamide441 235

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-oxo-2- ((1-(trifluoromethyl)cyclobutyl) amino)acetyl)-1H-pyrrole-3- carboxamide 455236

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(trifluoromethyl)cyclobutyl) amino)acetyl)-1H-pyrrole-3- carboxamide 454237

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl) amino)acetyl)-1H-pyrrole-3- carboxamide440 238

5-(2-((3,3-difluoro-1- methylcyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 436 239

N-((6-fluoropyridin-3-yl)-5-(2- (((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl) amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 485.1 240

N-(6-fluoropyridin-3-yl)-5-(2- (((1s,4s)-4-hydroxy-1-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxmaide 431.2 241

N-(4-fluoro-3-methylphenyl)- 1-(2-fluoroethyl)-5-(2-((1-methoxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide 450.2 242

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-(methylamino)-2-oxoacetyl)- 1H-pyrrole-3-carboxamide 346 243

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-(((3-(trifluoromethyl)-1,2,4- oxadiazol-5- yl)methyl)amino)acetyl)-1H-pyrrole-3-carboxamide 482 244

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-(((t-(trifluoromethyl)-4H- 1,2,4-triazol-3- yl)methyl)amino)acetyl)-1H-pyrrole-3-carboxamide 481 245

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1S,3R)-3-hydroxycyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 416.1 246

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1r,4r)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-triemthyl-1H-pyrrole-3-carboxamide 430.2 247

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((tetrahydro-2H-pyran-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide416.2 248

(4-(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)-2-methoxyphenyl)boronic acid 482.1 249

5-(2-((1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 464.1 250

5-(2-((4,4- difluorocyclohexyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 450.2 251

N-(3-chloro-4-fluorophenyl)-5- (2-(((1s,4s)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 450.1 252

N-(2-chloropyridin-4-yl)-5-(2- (((1s,4s)-4- hydroxycyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 433.1 253

N-(2-chloropyridin-4-yl)-1,2,4- trimethyl-5-(2-oxo-2-((4-(trifluoromethyl)tetrahydro- 2H-pyran-4-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 487.1 254

(3-(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2- oxoacetamido)phenyl)boronic acid 452255

(4-(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2- oxoacetamido)phenyl)boronic acid 452256

N-(4-fluoro-3-methylphenyl)- 5-(1-hydroxy-1H-enxo[c][1,5,2]oxazaborinine- 3-carbonyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 434 257

5-(2-((2-aminoethyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 375 258

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)- 2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 465 259

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)- 2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 465 260

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)- 2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 465 261

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)- 2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 465 262

5-(2-(cyclohexylamino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 414 263

N-(4-fluoro-3-methylphenyl)- 5-(2-((4- hydroxybicyclo[2.2.2]octan-1-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 457264

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((6-(trifluoromethyl)pyridin-3- yl)amino)acetyl)-1H-pyrrole-3- carboxamide477 265

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-(((1s,4s)- 4-morpholinocyclohexyl)amino)- 2-oxoacetyl)-1H-pyrrole-3- carboxamide 500266

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((6-morpholinopyridin-3- yl)amino)-2-oxoacetyl)-1H- pyrrol-3-carboxamide 495267

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1s,3s)-3-hydroxy-1-methylcyclobutyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 416.2 268

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1s,4s)-4-methoxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 444.2 269

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1r,4r)-4-methoxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 444.2 270

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2-morpholinoethyl)amino)-2- oxoacetyl)-1H-pyrrole-3- carboxamide 445.2 271

N-(2-fluoropyridin-4-yl)-1,2,4- trimethyl-5-(2-oxo-2-((4-(trifluoromethyl)tetrahydro- 2H-pyran-4-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 471.1 272

N-(2-fluoropyridin-4-yl)-1,2,4- trimethyl-5-(2-oxo-2-((tetrahydro-2H-thiopyran-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide419.1 273

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1r,4r)-4-hydroxy-1-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 444.2 274

(S)-N-(2-fluoropyridin-4-yl)- 1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide415.1 275

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-(prop-2-yn-1-ylamino)acetyl)- 1H-pyrrole-3-carboxamide 370.2 276

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-(pyridin-2-ylamino)acetyl)-1H- pyrrole-3-carboxamide 409 277

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methyltetrahydro-2H-pyran-4- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 430.2 278

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo2-((3-(trifluoromethyl)tetrahydrofuran- 3-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 470.2 279

(1s,4s)-4-(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2- oxoacetamido)cyclohexane-1-carboxylic acid 458.2 280

N-(4-fluoro-3-methylphenyl)- 5-(2-((4- (hydroxymethyl)tetrahydro-2H-pyran-4-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 446.1 281

5-(2-((3,3-dimethyltetrahydro- 2H-pyran-4-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 444.2 282

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1s,4s)-4-hydroxy-1-(trifluoromethyl)cyclohexyl) amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 498.2 283

(5-(2-(((1s,4s)-4- cyanocyclohexyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 439.2 284

1-ethyl-N-(4-fluoro-3- methylphenyl)-5-(2-(((1s,4s)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 444.2 285

1-ethyl-N-(4-fluoro-3- methylphenyl)-2,4-dimethyl-5- (2-oxo-2-((4-(trifluoromethyl)tetrahydro- 2H-pyran-4-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 498.2 286

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((2-oxopiperidin-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide 429.2 287

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1R,3R)-3-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 430.2 288

N-(4-fluoro-3-methylphenyl)- 5-(2-((3-hydroxy-1-(trifluoromethyl)cyclobutyl) amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 470.2 289

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl- 5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide 428.2 290

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-morpholinopropan-2- yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide459.3 291

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2-methyl-1-morpholinopropan-2- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 473.3 292

N-(4-fluoro-3-methylphenyl)- 5-(2-((2-(4-hydroxypiperidin-1-yl)ethyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 459.3 293

N-(3,4-difluorophenyl)-5-(2- ((3,4-difluorophenyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 448.2 294

N-(3,4-difluorophenyl)-1,2,4- trimethyl-5-(2-oxo-2-(pyridin-2-ylamino)acetyl)-1H-pyrrole- 3-carboxamide 413.2 295

N-(3,4-difluorophenyl)-5-(2- ((5-fluoropyridin-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 431.2 296

N-(3,4-difluorophenyl)-1,2,4- trimethyl-5-(2-oxo-2-(pyridin-3-ylamino)acetyl)-1H-pyrrole- 3-carboxamide 413.2 297

N-(3,4-difluorophenyl)-5-(2- ((6-fluoropyridin-3-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 431.2 298

5-(2-((4,4- difluorocyclohexyl)amino)-2- oxoacetyl)-N-(3,4-difluorophenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 454.2 299

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2- morpholino-2-oxoethyl)amino)-2-oxoacetyl)- 1H-pyrrole-3-carboxamide 459.2 300

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((2-(3-oxopiperazin-1- yl)ethyl)amino)acetyl)-1H- pyrrole-3-carboxamide458.2 301

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((3-morpholinopropyl)amino)-2- oxoacetyl)-1H-pyrrole-3- carboxamide 459.3302

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1S,3R)-3-hydroxy-2,2-dimethylcyclobutyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 430.2 303

N-(4-fluoro-3-methylphenyl)- 5-(2-((4- (isopropylcarbamoyl) tetrahydro-2H-pyran-4-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 501.3 304

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((3-methylisoxazol-5-yl)amino)-2- oxoacetyl)-1H-pyrrole-3- carboxamide 413.2305

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((5-methyl-1,3,4-oxadiazol-2- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 414.2 306

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-methyl-1H-pyrazol-3- yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide412.2 307

N-(4-fluoro-3-methylphenyl)- 5-(2-((1-(2-hydroxyethyl)-1H-pyrazol-3-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 442.2 308

N-(4-fluoro-3-methylphenyl)- 5-(2-((4- (hydroxymethyl)thiazol-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 445.2309

N-(3-chloro-4-fluorophenyl)- 1,2,4-trimethyl-5-(2-oxo-2-(pyridin-2-ylamino)acetyl)-1H- pyrrole-3-carboxamide 429.2 310

N-(3-chloro-4-fluorophenyl)-5- (2-((5-fluoropyridin-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 447.1311

N-(3-chloro-4-fluorophenyl)- 1,2,4-trimethyl-5-(22-oxo-2-(pyridin-3-ylamino)acetyl)-1H- pyrrole-3-carboxamide 429.1 312

N-(3-chloro-4-fluorophenyl)-5- (2-((6-fluoropyridin-3-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 447.2313

N-(3-chloro-4-fluorophenyl)-5- (2-((3,4- difluorophenyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 464.1 314

N-(3-chloro-4-fluorophenyl)-5- (2-((4,4- difluorocyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 470.2 315

N-(3,4-difluorophenyl)-1,2,4- trimethyl-5-(2-((4-methylthiazol-2-yl)amino)-2- oxoacetyl)-1H-pyrrole-3- carboxamide 433.1316

N-(3-chloro-4-fluorophenyl)- 1,2,4-trimethyl-5-(2-((4-methylthiazol-2-yl)amino)-2- oxoacetyl)-1H-pyrrole-3- carboxamide 449.1317

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((5-(trifluoromethyl)thiazol-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide483.2 318

1,2,4-trimethyl-5-(2-oxo-2- (pyridin-2-ylamino)acetyl)-N-(3,4,5-trifluorophenyl)-1H- pyrrole-3-carboxamide 431.1 319

5-(2-((5-fluoropyridin-2- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-N-(3,4,5- trifluorophenyl)-1H-pyrrole-3- carboxamide 449.1 320

1,2,4-trimethyl-5-(2-oxo-2- (pyridin-3-ylamino)acetyl)-N-(3,4,5-trifluorophenyl)-1H- pyrrole-3-carboxamide 431.2 321

5-(2-((6-fluoropyridin-3- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-N-(3,4,5- trifluorophenyl)-1H-pyrrole-3- carboxamide 449.1 322

5-(2-((3,4- difluorophenyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-N-(3,4,5-trifluorophenyl)-1H- pyrrole-3-carboxamide 466.1 323

1,2,4-trimethyl-5-(2-((4- methylthiazol-2-yl)amino)-2-oxoacetyl)-N-(3,4,5- trifluorophenyl)-1H-pyrrole-3- carboxamide 451.1324

5-(2-((4,4- difluorocyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-N-(3,4,5-trifluorophenyl)-1H- pyrrole-3-carboxamide 472.2 325

N-(6-fluoropyridin-3-yl)-1,2,4- trimethyl-5-(2-((4-methyltetrahydro-2H-pyran-4- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 417.2 326

N-(2-chloropyridin-4-yl)-1,2,4- trimethyl-5-(2-((4-methyltetrahydro-2H-pyran-4- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 433.2 327

5-(2-((2-(2,5-dimethylthiazol- 4-yl)ethyl)amnio)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 471.2 328

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((2-thiomorpholinoethyl)amino)acetyl)- 1H-pyrrole-3-carboxamide 461.2 329

5-(2-((2- (diethylamino)ethyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 431.3 330

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1R,3S)-3-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 430.2 331

N-(2-chloropyridin-4-yl)-1,2,4- trimethyl-5-(2-((2-methyl-1-morpholinopropan-2- yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide476.2 332

N-(3-chloro-4-fluorophenyl)- 1,2,4-trimethyl-5-(2-((2-methyl-1-morpholinopropan-2- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 493.2 333

N-(3-chloro-4-fluorophenyl)-5- (2-(((1r,4r)-4-hydroxy-1-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 464.2 334

N-(3-chloro-4-fluorophenyl)-5- (2-(((1s,4s)-4-hydroxy-1-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 464.2 335

N-(3,4-difluorophenyl)-5-(2- ((4- hydroxybicyclo[2.2.2]octan-1-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 460.2336

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2- (((1-propoxycyclohexyl)methyl) amino)acetyl)-1H-pyrrole-3- carboxamide 486.2337

5-(2-(((1- aminocyclohexyl)methyl)amino)- 2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl- 1H-pyrrole-3-carboxamide 443.2 338

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-((5-fluoropyridin-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 428.2339

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-oxo-2-(pyridin-3-ylamino)acetyl)-1H- pyrrole-3-carboxamide 410.2 340

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-((6-fluoropyridin-3-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 428.2341

5-(2-((3,4- difluorophenyl)amino)-2- oxoacetyl)-N-(5-fluoro-5-methylpyridin-3-yl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 445.2 342

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-((4-methylthiazol-2-yl)amino)-2- oxoacetyl)-1H-pyrrole-3- carboxamide 430.1343

5-(2-((4,4- difluorocyclohexyl)amino)-2- oxoacetyl)-N-(6-fluoro-5-methylpyridin-3-yl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 451.2 344

N-(6-fluoro-5-methylpyridin-3- yl)-5-(2-(((1s,4s)-4-methoxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 445.3 345

N-(2-chloropyridin-4-yl)-5-(2- (((1s,4s)-4- methoxycyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 447.2 346

5-(2-((2-(1H-imidazol-1- yl)ethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-1H-pyrrole-3- carboxamide426.2 347

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((2-(thiophen-2- yl)ethyl)amino)acetyl)-1H- pyrrole-3-carboxamide 442.2 348

5-(2-((2-(4H-1,2,4-triazol-3- yl)ethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-1H-pyrrole-3- carboxamide427.2 349

N4-(4-fluoro-3-methylphenyl)- 1,3,5-trimethyl-N2-(2-methyl-1-morpholinopropan-2-yl)-1H- pyrrole-2,4-dicarboxamide 445.1 350

N-(6-fluoropyridin-3-yl)-1,2,4- trimethyl-5-(2-((2-methyl-1-morpholinopropan-2- yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide460.3 351

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-((2-methyl-1-morpholiinopropan-2- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 474.3 352

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2- methyl-2-morpholinopropyl)amino)-2- oxoacetyl)-1H-pyrrole-3- carboxamide 473.3353

N-(44-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-methylazepan-4-yl)amino)-2- oxoacetyl)-1H-pyrrole-3- carboxamide 443.2354

5-(2-((1-acetylpiperidin-4- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 457.3355

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2- methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 483.2 356

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2-(5-methyl-1,3,4-thiadiazol-2- yl)ethyl)amino0-2-oxoacetyl)-1H-pyrrole-3-carboxamide 458.2 357

N-(3-chloro-4-fluorophenyl)-5- (2-((4- hydroxybicyclo[2.2.2]octan-1-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 476.2358

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1- (methoxymethyl)cyclohexyl)methyl)amino)-2-oxoacetyl)- 1,2,4-trimethyl-1H-pyrrole-3- carboxamide472.2 359

N-(4-fluoro-3-methylphenyl)- 5-(2-((1- (hydroxymethyl)cyclopentyl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 430.2 360

5-(2-((1- carbamoylcyclopropyl)amino)- 2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1-(2- hydroxyethyl)-2,4-dimethyl- 1H-pyrrole-3-carboxamide361

(R)-5-(2-((1-amino-3,3- dimethyl-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1-(2-hydroxyethyl)-2,4-dimethyl- 1H-pyrrole-3-carboxxamide 362

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(5-fluoropyridin-2-yl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 363

5-(2-(tert-butylamino)-2- oxoacetyl)-4-chloro-N-(4-fluoro-3-methylphenyl)-1,2- dimethyl-1H-pyrrole-3- carboxamide 408.2 364

4-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-1,2-dimethyl-1H- pyrrole-3-carboxamide422.2 365

4-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-1,2-dimethyl-1H-pyrrole-3- carboxamide 422.1 366

4-chloro-5-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro- 3-methylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide 502.1 367

4-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-(((1R,2S)-2-hydroxycyclopentyl)aminO)- 2-oxoacetyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide 466.2 368

(S)-4-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((1-hydroxybutan-2-yl)amino0-2- oxoacetyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide 454.2 369

5-(2-(tert-butylamino)-2- oxoacetyl)-4-chloro-1,2- dimethyl-N-(3,4,5-trifluorophenyl)-1H-pyrrole-3- carboxamide 428.1 370

5-(2-(tert-butylamino)-2- oxoacetyl)-4-chloro-N-(3-chloro-4-fluorophenyl)-1,2- dimethyl-1H-pyrrole-3- carboxamide 426.1 371

5-(2-(tert-butylamino)-2- oxoacetyl)-4-chloro-N-(6-fluoro-5-methylpyridin-3-yl)- 1,2-dimethyl-1H-pyrrole-3- carboxamide439.2 372

4-chloro-5-(2-((2-hydroxy-2- methylpropyl)amino)-2-oxoacetyl)-1,2-dimethyl-N- (3,4,5-trifluorophenyl)-1H-pyrrole-3-carboxamide 444.1 373

4-chloro-5-(2-((1-hydroxy-2- methylpropan-2-yl)amino)-2-oxoacetyl)-1,2-dimethyl-N- (3,4,5-trifluorophenyl)-1H-pyrrole-3-carboxamide 444.1 374

4-chloro-5-(2-(((1R,2S)-2- hydroxycyclopentyl)amino)-2-oxoacetyl)-1,2-dimethyl-N- (3,4,5-trifluorophenyl)-1H-pyrrole-3-carboxamide 456.1 375

4-chloro-5-(2-((3,3-difluoro-1- methylcyclobutyl)amino)-2-oxoacetyl)-N-(3,4- difluorophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide 458.1 376

4-chloro-N-(3,4- difluorophenyl)-1,2-dimethyl- 5-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl) amino)acetyl)-1H-pyrrole-3- carboxamide460.2 377

N-(3,4-difluorophenyl)-4- methoxy-1,2-dimethyl-5-(2- oxo-2-((1-(trifluoromethyl)cyclopropyl) amino)acetyl)-1H-pyrrole-3- carboxamide464.3 378

N-(3,4-difluorophenyl)-4- methoxy-1,2-dimethyl-5-(2- oxo-2-((1-(trifluoromethyl)cyclobutyl) amino)acetyl)-1H-pyrrole-3- carboxamide474.2 379

5-(2-((3,3-difluoro-1- methylcyclobutyl)amino)-2- oxoacetyl)-N-(3,4-difluorophenyl)-4-methoxy- 1,2-dimethyl-1H-pyrrole-3- carboxamide 456.2380

5-(2-tert-butylamino)-2- oxoacetyl)-N-(3,4- difluorophenyl)-4-methoxy-1,2-dimethyl-1H-pyrrole-3- carboxmaide 408.2 381

N-(3,4-difluorophenyl)-5-(2- ((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-4- methoxy-1,2-dimethyl-1H- pyrrole-3-carboxamide424.2 382

N-(3,4-difluorophenyl)-5-(2- ((2-hydroxy-2- methylpropyl)amino)-2-oxoacetyl)-4-methoxy-1,2- dimethyl-1H-pyrrole-3- carboxamide 424.2 383

N-(3,4-difluorophenyl)-5-(2- (((1s,4s)-4- hydroxycyclohexyl)amino)-2-oxoacetyl)-4-methoxy-1,2- dimethyl-1H-pyrrole-3- carboxamide 449.2 384

N-(3,4-difluorophenyl)-5-(2- (((1R,2S)-2- hydroxycyclopentyl)amino)-2-oxoacetyl)-4-methoxy)-1,2- dimetthyl-1H-pyrrole-3- carboxamide 436.2 385

(S)-N-(3,4-difluorophenyl)-5- (2-((1-hydroxybutan-2-yl)amino)-2-oxoacetyl)-4- methoxy-1,2-dimethyl-1H- pyrrole-3-carboxamide424.2 386

5-(2-(tert-butylamino)-2- oxoacetyl)-2-chloro-N-(4-fluoro-3-methylphenyl)-1,4- dimethyl-1H-pyrrole-3- carboxamide 481.2 387

2-chloro-5-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro- 3-methylphenyl)-1,4-dimethyl-1H-pyrrole-3-carboxamide 494.1 388

2-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-1,4-dimethyl-1H- pyrrole-3-carboxamide447.2 389

(S)-2-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((1-hydroxybutan-2-yl)amino)-2- oxoacetyl)-14-dimethyl-1H-pyrrole-3-carboxamide 447.2 390

2-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-(((1R,2S)-2-hydroxycyclopentyl)amino)- 2-oxacetyl)-1,4-dimethyl-1H-pyrrole-3-carboxamide 460.2 391

2-chloro-N-(44-fluoro-3- methylphenyl)-5-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-1 4-dimethyl-1H-pyrrole-3- carboxamide 447.2 392

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3-cyano-4-fluorophenyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 411.1 393

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 401.1 394

N-(4-fluoro-3-methylphenyl)- 3-(2-((2-methyl-1-(3-methyl-1,2,4-oxadiazol-5- yl)propyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 482.2 395

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3-chloro-5-fluorophenyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 418.9 396

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3,4,5- trifluorophenyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 421.9 397

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3,4-difluoro-5-metthylphenyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 418 398

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3,4- difluorophenyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 403.9 399

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3-chloro-4-fluorophenyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 419.9 400

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3- (difluoromethyl)-4-fluorophenyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 435.9 401

3-(2-(((2S,3R)-1-amino-3- hydroxy-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 444.9 402

N-(4-fluoro-3-methylphenyl)- 3-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl) amino)acetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 451.9 403

N-(4-fluoro-3-methylphenyl)- 3-(2-oxo-2-((1-(trifluoromethyl))cyclobutyl) amino)acetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 465.9 404

3-(2-((3,3-difluoro-1- methylcyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 447.9 405

N-(4-fluoro-3-metthylphenyl)- 3-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)- 5,6,7,8-tetrahydroindolizine-1- carboxamide413.9 406

3-(2-(1-amino-2-methyl-1- oxopropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 429.0 407

(S)-N-(4-fluoro-3- methylphenyl)-3-(2-oxo-2- ((1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,6,7,78- tetrahydroindolizine-1- carboxamide 439.9 408

(R)-N-(4-fluoro-3- methylphenyl)-3-(2-oxo-2- ((1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 440.1 409

N-(4-fluoro-3-methylphenyl)- 3-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2- yl)amino)acetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 454.1 410

N-(4-fluoro-3-methylphenyl)- 3-(2-((1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 427.9411

N-(4-fluoro-3-methylphenyl)- 3-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolixzine-1-carboxamide 416.0 412

N-(4-fluoro-3-methylphenyl)- 3-(2-(isopropylamino)-2-oxoacetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 386.1 413

N-(4-fluoro-3-methylphenyl)- 3-(2-((2-(5-methylthiazol-2-yl)propan-2-yl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 483.2 414

N-(4-fluoro-3-methylphenyl)- 3-(2-((1-(3-cmethyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-2- oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 453.2 415

(R)-3-(2-((2,3- dihydroxypropyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 418.1 416

(S)-3-(2-((2,3- dihydroxypropyl)amino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 418.1 417

3-(2-(((2S,3S)-1,3- dihydroxybutan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 432.1 418

N-(4-fluoro-3-methylphenyl)- 3-(2-((1-(3-methyl-1,2,4- oxadiazol-5-yl)cyclopropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroidolizine-1-carboxamide 466.1 419

N-(4-fluoro-3-methylphenyl)- 3-(2-((2-hydroxy-2- methylpropyl)amino)-2-oxoacetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 416.1 420

N-(4-fluoro-3-methylphenyl)- 3-(2-((1- (hydroxymethyl)cyclopropyl)amino)-2-oxoacetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 414.1421

3-(2-(2-amino-6,7- dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 482.1 422

(R)-2-(2-(1-((4-fluoro-3- methylphenyl)carbamoyl)-5,6,7,8-tetrahydroindolizin-3- yl)-2-oxoacetamido)-3,3- dimethylbutanoicacid 458.1 423

N-(3-chloro-5-fluorophenyl)-3- (2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 436.0 424

3-(2-((1-hydroxy-2- methylpropan-2-yl)amino)-2- oxoacetyl)-N-(3,4,5-trifluorophenyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 438.1 425

N-(3,4-difluoro-5- methylphenyl)-3-(2-((1- hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)- 5,6,7,8-tetrahydroindolizine-1- carboxamide434.2 426

N-(3,4-difluorophenyl)-3-(2- ((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)- 5,6,7,8-tetrahydroindolizine-1- carboxamide420.1 427

N-(3-chloro-4-fluorophenyl)-3- (2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 435.8 428

(R)-3-(2-((3,3-difluorobutan-2- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)- 5,6,7,8-tetrahydroindolizine--1 carboxamide436.1 429

N-(3-(difluoromethyl)-4- fluorophenyl)-3-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 452.0 430

(S)-N-(4-fluoro-3- methylphenyl)-3-(2-((1-(3- methyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-2-oxoacetyl)- 5,6,7,8-tetrahydroindolizine-1-carboxamide 454.1 431

(R)-N-(4-fluoro-3- methylphenyl)-3-(2-((1-(3- methyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-2-oxoacetyl)- 5,6,7,8-tetrahydroindolizine-1-carboxamide 454.1 432

3-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro- 3-methylphenyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 464.0 433

3-(2-(((2R,3R)-1,3- dihydroxybutan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 432.1 434

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(4-ffluoro-3-methylphenyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1- carboxamide414.1 435

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3-cyano-4-fluorophenyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1- carboxamide425.1 436

N-(4-fluoro-3-methylphenyl)- 3-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 430.1 437

3-(2-((2-(3- ((dimethylamino)methyl)- 1,2,4-oxadiazol-5-yl)propan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-2- methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 525.2 438

N-(4-fluoro-3-methylphenyl)- 3-(2-(((1r,3r)-3-hydroxycyclobutyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 428.1 439

N-(4-fluoro-3-methylphenyl)- 3-(2-(((3S,4R)-4- hydroxytetrahydrofuran-3-yl)amino)-2-oxoacetyl)-2- methyl-5,6,7,8- tetrahydroindolizine-1-carboxamide 444.1 440

N-(4-fluoro-3-methylphenyl)- 3-(2-(((1S,2R)-2-hydroxycyclopentyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 442.1 441

3-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro- 3-methylphenyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 478.1 442

N-(4-fluoro-3-methylphenyl)- 3-(2-((1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1-carboxamide 442.1 443

N-(4-fluoro-3-methylphenyl)- 3-(2-((3-hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetreahydroindolizine-1- carboxamide 444.1 444

N-(4-fluoro-3-methylphenyl)- 3-(2-((2-hydroxy-2- methylpropyl)amino)-2-oxoacetyl)-2-methyl-5,6,7,8- tetrahydroindolizine-1- carboxamide 430.1445

N-(4-fluoro-3-methylphenyl)- 3-(2-((1- (hydroxymethyl)cyclopropyl)amino)-2-oxoacetyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1-carboxamide 428.1 446

(S)-N-(3-chloro-4- fluorophenyl)-2-methyl-3-(2-((1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl)amino)-2- oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 488.0 447

(R)-N-(3-chloro-4- fluorophenyl)-2-methyl-3-(2-((1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl)amino)-2- oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 488.0 448

3-(2-(((2-aminothiazol-5- yl)methyl)amino)-2- oxoacetyl)-N-(3-chloro-4-fluorophenyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1- carboxamide490.0 449

N-(3-chloro-4-fluorophenyl)-3- (2-(((1r,3r)-3-hydroxycyclobutyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindoliziine-1- carboxamide 448.1 450

N-(3-chloro-4-fluorophenyl)-3- (2-(((3S,4R)-4- hydroxytetrahydrofuran-3-yl)amino)-2-oxoacetyl)-2- methyl-5,6,7,8- tetrahydroindolizine-1-carboxamide 464.1 451

N-(3-chloro-4-fluorophenyl)-3- (2-(((1S,2R)-2-hydroxycyclopentyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 462.1 452

N-(3-chloro-4-fluorophenyl)-3- (2-((1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1-carboxamide 462.1 453

N-(3-chloro-4-fluorophenyl)-3- (2-((1- (hydroxymethyl)cyclopropyl)amino)-2-oxoacetyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1-carboxamide 448.0 454

(R)-N-(3,4-difluorophenyl)-2- methyl-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)5,6,7,8-tetrahydroindolizine-1- carboxamide 472.1 455

3-(2-(((2-aminothiazol-5- yl)methyl)amino)-2- oxoacetyl)-N-(3,4-difluorophenyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1- carboxamide474.1 456

N-(3,4-difluorophenyl)-3-(2- (((1r,3r)-3- hydroxycyclobutyl)amino)-2-oxoacetyl)-2-methyl-5,6,7,8- tetrahydroindolizine-1- carboxamide 432.1457

N-(3,4-difluorophenyl)-3-(2- (((3S,4R)-4- hydroxytetrahydrofuran-3-yl)amino)-2-oxoacetyl)-2- methyl-5,6,7,8- tettrahydroindolizine-1-carboxamide 448.1 458

N-(3,4-difluorophenyl)-3-(2- (((1S,2R)-2- hydroxycyclopentyl)amino)-2-oxoacetyl)-2-methyl-5,6,7,8- tetrahydroindolizine-1- carboxamide 446.1459

3-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4- difluorophenyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 482.1 460

N-(3,4-difluorophenyl)-3-(2- ((1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-2-methyl- 5,6,7,8-tetrahydroindoline-1- carboxamide446.1 461

N-(3,4-difluorophenyl)-3-(2- ((3-hydroxy-2,2- dimethylpropyl)amino)-2-oxoacetyl)-2-methyl-5,6,7,8- tetrahydroindolizine-1- carboxamide 448.1462

N-(3,4-difluorophenyl)-3-(2- ((2-hydroxy-2- methylpropyl)amino)-2-oxoacetyl)-2-methyl-5,6,7,8- tetrahydroindolizine--1 carboxamide 434.2463

N-(3,4-difluorophenyl)-3-(2- ((1- (hydroxymethyl)cyclopropyl)amino)-2-oxoacetyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1-carboxamide 432.1 464

(S)-N-(3,4-difluorophenyl)-2- methyl-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 472.1 465

N-(3-chloro-4-fluorophenyl)-3- (2-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-2-methyl-5,,6,7,8-tetrahydroindolizine-1- carboxamide 498.1 466

N-(3-chloro-4-fluorophenyl)-3- (2-((3-hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 464.1 467

N-(3-chloro-4-fluorophenyl)-3- (2-((2-hydroxy-2- methylpropyl)amino)-2-oxoacetyl)-2-methyl-5,6,7,8- tetrahydroindolizine-1- carboxamide 450.1468

N-(6-fluoro-5-methylpyridin-3- yl)-2-methyl-3-(2-oxo-2-((1,1,1-trifluoro-2- methylpropan-2- yl)amino)acetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 469.2 469

(R)-N-(6-fluoro-5- methylpyridin-3-yl)-2-methyl- 3-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 455.2 470

(S)-N-(6-fluoro-5- methylpyridin-3-yl)-2-methyl- 3-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-5,6,7,8- tetrahydroindolizine--1carboxamide 455.2 471

(S)-N-(6-fluoro-5- methylpyridin-3-yl)-2-methyl-3-(2-((1-(3-methyl-1,2,4- oxadiazol-5-yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 469.2 472

(R)-N-(6-fluoro-5- methylpyridin-3-yl)-2-methyl-3-(2-((1-(3-methyl-1,2,4- oxadiazol-5-yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 469.2 473

3-(2-(((2-aminothiazol-5- yl)methyl)amino)-2- oxoacetyl)-N-(6-ffluoro-5-methylpyridin-3-yl)-2-methyl- 5,,6,7,8-tetrahydroindolizine--1carboxamide 471.1 474

3-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(6-fluoro- 5-methylpyridin-3-yl)-2-methyl-5,6,7,8- tetrahydroindolizine-1- ccarboxamide 478.8 475

(S)-3-(2-(sec-butylamino)-2- oxoacetyl)-N-(6-fluoro-5-methylpyridin-3-yl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1-carboxamide 415.3 476

N-(6-fluoro-5-methylpyridin-3- yl)-3-(2-((3-hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 445.2 477

N-(6-fluoro-5-methylpyridin-3- yl)-3-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 431.1 478

N-(6-fluoro-5-methylpyridin-3- yl)-3-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindoliizine-1- carboxamide 430.9 479

N-(3-chloro-4-ffluorophenyl)-3- (2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 480

(S)-N-(4-fluoro-3- methylphenyl)-2-methyl-3-(2-oxo-2-((1,1,1-trifluoropropan- 2-yl)amino)acetyl)-5,6,7,8-tetrahydroindolizine--1 carboxamide 481

3-(2-((1-amino-2-methyl-1- oxopropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 482

3-(2-((3,3-difluoro-1- methylcyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 483

3-(2-(((2S,3R)-1-amino-3- hydroxy-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-2- methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 484

(R)-2-(2-(1-((4-fluoro-3- methylphenyl)carbamoyl)-2- methyl-5,6,7,8-tetrahydroindolizin-3-yl)-2- oxoacetamido)-3,3- dimethylbutanoic acid485

(R)-3-(2-((2,2-ddimethyl-1-(1H- tetrazol-5-yl)propyl)amino)-2-oxoacetyl)-N-(44-fluoro-3- methylphenyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 486

3-(2-((1-carbamoyl-3,3- difluorocyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 487

3-(2-((3,3-difluoro-1-(1H- 1,2,3-triazol-4- yl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 488

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3- (difluoromethyl)-4-fluorophenyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1- carboxamide 489

3-(2-(tert-butylamino)-2- oxoacetyl)-2-chloro-N-(4-fluoro-3-methylphenyl)- 5,6,7,8-tetrahydroindolizine-1- carboxamide433.7 490

2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 450.1 491

2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-((1-(hydroxymethyl)cyclopropyrl) amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 448.0 492

2-chloro-N-(3,4- difluorophenyl)-3-(2-((1- hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)- 5,6,7,8-tetrahydroindolizine-1- carboxamide454.1 493

(S)-2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-((2-methyl-1-(3-methyl-1,2,4- oxadiazol-5-yl)propyl)amino)-2-oxoacetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 516.1 494

(S)-2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizinee-1- carboxamide 448.1 495

(R)-2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindoliizine-1- carboxamide 448.1 496

2-chloro-3-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro- 3-methylphenyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 498.1 497

2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindoliine-1-carboxamide 450.0 498

2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-((3- hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 464.0 499

2-chloro-N-(3,4- difluorophenyl)-3-(2-((1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 466.1500

2-chloro-N-(3-chloro-5- fluorophenyl)-3-(2-((1-(hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 482.0 501

2-chloro-N-(3-chloro-4- fluorophenyl)-3-(2-((1-(hydroxymethyl)cyclopropyl) amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine--1 carboxamide 468.0 502

2-chloro-N-(3,4- difluorophenyl)-3-(2-((1- (hydroxymethyl)cyclopropyl)amino)-2-oxoacetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 452.0503

3-(2-(((2-aminothiazol-5- yl)methyl)amino)-2- oxoacetyl)-2-chloro-N-(4-fluoro-3-methylphenyl)- 5,6,7,8-tetrahydroindolizine-1- carboxamide490.0 504

2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-((1-(hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 462.0 505

2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-(((3S,4R)-4-hydroxytetrahydrofuran-3- yl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 464.0 506

2-chloro-N-(4-fluoro-3- methylphenyl)-3-(2-(((1S,2R)-2-hydroxycyclopentyl)amino)- 2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 462.0 507

2-chloro-3-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(6-fluoro- 5-methylpyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 498.1 508

2-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-3-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-5,6,7,8-tettrahydroindolizine-1- carboxamide 451.1 509

(S)-2-chloro-N-(2- fluororpyridin-4-yl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-55- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindoliznie-1- carboxamide 475.1 510

(R)-2-chloro-N-(2- fluoropyridin-4-yl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 475.0 511

2-chloro-3-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(2- fluoropyridin-4-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 485.0 512

2-chloro-N-(2-fluoropyridin-4- yl)-3-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 437.1 513

2-chloro-N-(3-chloro-4- fluorophenyl)-3-(2-(((3S,4R)-4-hydroxytetrahydrofuran-3- yl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 484.0 514

2-chloro-N-(3-chloro-4- fluorophenyl)-3-(2-(((1S,2R)-2-hydroxycyclopentyl)amino)- 2-oxoacettyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 482.0 515

2-chloro-N-(3-chloro-4- fluorophenyl)-3-(2-((3,3- difluoro-1-(hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 518.0 516

(S)-2-chloro-N-(3,4- difluorophenyl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine--1 carboxamide 492.1 517

(R)-2-chloro-N-(3,4- difluorophenyl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamidde 492.1 518

2-chloro-N-(3,4- difluorophenyl)-3-(2- (((3S,4R)-4-hydroxytetrahydrofuran-3- yl)amino)-2-oxoacetyl)-5,6,7,8-tetrahdyroindolinzie-1- carboxamide 468.0 519

2-chloro-N-(3,4- difluorophenyl)-3-(2-(((1S,2R)-2-hydroxycyclopentyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindoliznie-1-carboxamide 466.1 520

2-chloro-3-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4- difluorophenyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 502.0 521

(S)-2-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 489.1 522

(R)-2-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 489.1 523

(S)-2-chloro-N-(3-chloro-4- fluorophenyl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 508.0 524

(R)-2-chloro-N-(3-chloro-4- fluorophenyl)-3-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 508.0 525

2-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-3-(2-((3- hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 465.1 526

2-chloro-N-(2-fluoropyridin-4- yl)-3-(2-((3-hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 451.1 527

2-chloro-N-(3-chloro-4- fluorophenyl)-3-(2-((3- hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 484.1 528

2-chloro-N-(3,4- difluorophenyl)-3-(2-((3- hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 468.1 529

2-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-3-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 451.1 530

2-chloro-N-(22-fluoropyridin-4- yl)-3-(22-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 437.1 531

2-chloro-N-(3-chloro-4- fluorophenyl)-3-(2-(((1r,3r)-3-hydroxycyclobutyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 468.1 532

2-chloro-N-(3-chloro-4- fluorophenyl)-3-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 470.0 533

2-chloro-N-(3,4- difluorophenyl)-3-(2-(((1r,3r)-3-hydroxycyclobutyl)amino)-2- oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 452.1 534

2-chloro-N-(3,4- difluorophenyl)-3-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-5,6,7,8- tetrahydroindolizine--1carboxamide 454.1 535

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(3-chloro-4-fluorophenyl)-2,3-dihydro-1H- pyrrolizine-7-carboxamide 406.1 536

5-(2-(tert-butylamino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2,3-dihydro- 1H-pyrrolizine-7-carboxamide 386.2 537

N-(4-fluoro-3-methylphenyl)- 5-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 401.9 538

5-(2-amino-2-oxoacetyl)-N-(3- chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H- pyrrolizine-7-carboxamide 539

5-(2-(tert-butylamino)-2- oxoacetyl)-6-chloro-N-(4-fluoro-3-methylphenyl)-2,3- dihydro-1H-pyrrolizine-7- carboxamide 420.2540

6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 436.0 541

6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((1-(hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 448.1 542

6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((1-(hydroxymethyl)cyclopropyl) amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 434.1 543

(S)-6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((2-methyl-1-(3-methyl-1,2,4- oxadiazol-5-yl)propyl)amino)-2-oxoacetyl)-2,3-dihydro-1H- pyrrolizine-7-carboxamide 502.0 544

(R)-6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((2-methyl-1-(3-methyl-1,2,4- oxadiazol-5-yl)propyl)amino)-2-oxoacetyl)-2,3-dihydro-1H- pyrrolizine-7-carboxamide 502.0 545

(S)-6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 474.0 546

(R)-6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 474.0 547

6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-(((1S,2R)-2-hydroxycyclopentyl)amino)- 2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 448.1 548

6-chloro-5-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro- 3-methylphenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 484.0 549

6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((3- hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 450.0 550

6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboamide 436.1 551

6-chloro-N-(3,4- difluorophenyl)-5-(2-(((1r,3r)-3-hydroxycyclobutyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 437.9 552

5-(2-(((2-aminothiazol-5- yl)methyl)amino)-2- oxoacetyl)-6-chloro-N-(4-fluoro-3-methylphenyl)-2,3- dihydro-1H-pyrrolizine-7- carboxamide 476.0553

(S)-6-chloro-N-(3-chloro-4- fluorophenyl)-5-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 494.0 554

(R)-6-chloro-N-(3-chloro-4- fluorophenyl)-5-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 494.0 555

6-chloro-N-(3-chloro-4- fluorophenyl)-5-(2-(((1r,3r)-3-hydroxycyclobutyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 454.1 556

6-chloro-N-(3-chloro-4- fluorophenyl)-5-(2-((3- hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 470.0 557

6-chloro-N-(3-chloro-4- fluorophenyl)-5-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 456.0 558

6-chloro-N-(3,4- difluorophenyl)-5-(2-((1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-2,3-dihydro- 1H-pyrrolizine-7-carboxamide 452.0 559

6-chloro-N-(3,4- difluorophenyl)-5-(2-((3- hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 454.0 560

6-chloro-N-(3,4- difluorophenyl)-5-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 440.1 561

6-chloro-N-(3,4- difluorohphenyl)-5-(2-((1- (hydroxymethyl)cyclopropyl)amino)-2-oxoacetyl)-2,3- dihydro-1H-pyrrolizine-7- carboxamide 438.1 562

5-(2-(((2-aminothiazol-5- yl)methyl)amino)-2- oxoacetyl)-6-chloro-N-(3-chloro-4-fluorophenyl)-2,3- dihydro-1H-pyrrolizine-7- carboxamide 495.9563

6-chloro-N-(3-chloro-4- fluorophenyl)-5-(2-(((3S,4R)-4-hydroxytetrahydrofuran-3- yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 470.0 564

6-chloro-N-(3-chloro-4- fluorophenyl)-5--(2-(((1S,2R)-2-hydroxycyclopentyl)amino)- 2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 468.0 565

6-chloro-N-(3-chloro-4- fluorophenyl)-5-(2-((1-(hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 468.0 566

6-chloro-N-(3-chloro-4- fluorophenyl)-5-(2-((1-(hydroxymethyl)cyclopropyl) amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 454.0 567

(R)-6-chloro-N-(3,4- difluorophenyl)-5-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 478.1 568

(S)-6-chloro-N-(3,4- difluorophenyl)-5-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 478.0 569

5-(2-(((2-aminothiazol-5- yl)methyl)amino)-2-oxoacetyl)-6-chloro-N-(3,4- difluorophenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 480.1 570

6-chloro-N-(3,4- difluorophenyl)-5-(22- (((3S,4R)-4-hydroxytetrahydrofuran-3- yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 454.1 571

6-chloro-N-(3,4- difluorophenyl)-5-(2- (((1S,2R)-2-hydroxycyclopentyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 452.0 572

6-chloro-N-(4-fluoro-3- methylphenyl)-5-(2-(((3S,4R)-4-hydroxytetrahydrofuran-3- yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 450.0 573

6-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-5-(2-oxo-2-((1,1,1-trifluoro-2- methylpropan-2- yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 475.0 574

(S)-6-chloro-N-(6-ffluoro-5- methylpyridin-3-yl)-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-2,3-dihydro-1H-pyrroliine-7-carboxamide 461.1 575

6-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-5-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 437.1 576

(R)-6-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 461.0 577

6-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-5-(2-((3- hydroxy-2,2-dimethylpropyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 451.1 578

6-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-5-(2-((2- hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 437.1 579

6-chloro-5-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(6-fluoro- 5-methylpyridin-3-yl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 485.1 580

6-chloro-N-(3-chloro-4- fluorophenyl)-5-(2-((3,3- difluoro-1-(hydroxymethyl)cyclobutyl)amino)- 2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 504.0 581

6-chloro-5-(2-((3,3-difluoro-1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-N-(3,4- difluorophenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide 488.0 582

6-(2-(tert-butylamino)-2- oxoacetyl)-N-(3-cyano-4-fluorophenyl)-3,4-dihydro-1H- pyrrolo[2,1-c][1,4]oxazine-8- carboxamide412.8 583

6-(2-(tert-butylamino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-3,4-dihydro- 1H-pyrrolo[2.1-c][1,4]oxazine- 8-carboxamide401.9 584

7-chloro-N-(3,4- difluorophenyl)-6-(2-((1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-3,4-dihydro- 1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide 468.0 585

6-(2-((2-methyl-1- (methylamino)-1-oxopropan-2-yl)amino)-2-oxoacetyl)-N- (3,4,5-trifluorophenyl)-3,4-dihydro-1H-pyrrolo[2,1- c][1,4]oxazine-8-carboxamide 586

N-(4-fluoro-3-methylphenyl)- 6-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-7-methyl-3,4-dihydro-1H-pyrrolo[2,1- c][1,4]oxazine-8-carboxamide 587

tert-butyl 6-(2-(tert- butylamino)-2-oxoacetyl)-8- ((4-fluoro-3-methylphenyl)carbamoyl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate 501.0 588

6-(2-(tert-butylamino)-2- oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,3,4- tetrahydropyrrolo[1,2- a]pyrazine-8-carboxamide401.0 589

6-(2-(tert-butylamino)-2- oxoacetyl)-N-(4-fluoro-3- methylphenyl)-2-(methylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide 479.0 590

2-acetyl-6-(2-(tert- butylamino)-2-oxoacetyl)N-(4-fluoro-3-methylphenyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide 443.0 591

2-acetyl-N-(3,4-difluoro-5- methylphenyl)-6-(2-((1-hydroxy-2-methylpropan-2- yl)amino)-2-oxoacetyl)-7- methyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine-8-carboxamide 592

6-(2-((1-(1H-1,2,3-triazol-4- yl)cyclopropyl)amino)-2-oxoacetyl)-N-(3,4-difluoro-5- methylphenyl)-2,7-dimethyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine-8-carboxamide 593

3-(2-(tert-butylamino)-2- oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6,7,8,9- tetrahydro-5H-pyrrolo[1,2-a]azepine-1-carboxamide 594

N-(3-chloro-4-fluorophenyl)-3- (2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-2-methyl-6,7,8,9- tetrahdyro-5H-pyrrolo[1,2- a]azepine-1-carboxamide 595

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-(morpholinomethyl)cyclopentyl) amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 499.3 596

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-(morpholinomethyl)cyclohexyl) amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 513.3 597

N-(4-fluoro-3-methylphenyl)- 5-(2-((1-(4-hydroxypiperidin-1-yl)-2-methyl-1-oxopropan-2- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 501.3 598

N-(4-fluoro-3-methylphenyl)- 5-(2-((6- hydroxyspiro[3.3]heptan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 442.2599

N-(4-fluoro-3-methylphenyl)- 5-(2-((1- (hydroxymethyl)cyclohexyl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 444.1 600

N-(3-chlorophenyl)-5-(2-((1- hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 406.2601

N-(3-chlorophenyl)-1,2,4- trimethyl-5-(2-((2-methyl-1-morpholinopropan-2- yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide475.2 602

N-(3-chlorophenyl)-5-(2- (((1s,4s)-4- hydroxycyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 432.2 603

(R)-N-(3-chlorophenyl)-1,2,4- trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide 430.1 604

N-(3-chlorophenyl)-1,2,4- trimethyl-5-(3-oxo-2-((4-(trifluoromethyl)tetrahydro- 2H-pyran-4-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 486.1 605

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-((4-((1,1,1- trifluoropropan-2- yl)carbamoyl)tetrahydro-2H-pyran-4-yl)amino)acetyl)-1H- pyrrole-3-carboxamide 555.1 606

N-(6-fluoro-5-methylpyridin-3- yl)-1,2,4-trimethyl-5-(2-((2-methyl-4,5,6,7- tetrahydrobenzo[d]thiazol-7- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 484.2 607

N-(2-fluoropyridin-4-yl)-1,2,4- trimethyl-5-(2-((2-methyl- 4,5,6,7-tetrahydrobenzo[d]thiazol-7- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 470.2 608

N-(4-fluoro-3-methylphenyl)- 5-(2-((5-hydroxytetrahydro-2H-pyran-3-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 432.2 609

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-methyl-2-oxopiperidin-4- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 443.2 610

5-(2-((2,6-dioxopiperidin-4- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 443.2611

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-((5-oxopyrrolidin- 3-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 415.2 612

5-(2-((1-acetyl-4- methylpiperidin-4-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 471.2 613

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4- methyl-1-(methylsulfonyl)piperidin-4- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 507.2 614

N-ethyl-4-(2-(4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)-4- methylpiperidine-1-carboxamide 500.3 615

N-(3-chlorophenyl)-5-(2- (((1r,4r)-4-hydroxy-1-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 446.2 616

N-(3,4-difluorophenyl)-5-(2- ((1- (hydroxymethyl)cyclohexyl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 448.2 617

N-(4-fluoro-3-methylphenyl)- 5-(2-((3-hydroxy-2,3-dimethylbutan-2-yl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 432.2 618

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1S,3S)-3-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 430.2 619

N-(4-fluoro-3-methylphenyl)- 5-(2-((1r,3r)-3-hydroxy-1-methylcyclobutyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 416.2 620

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1S,3S)-3-hydroxy-7-oxaspiro[3.5]nonan-1- yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 472.2 621

(R)-5-(2-((4,4-dimethyl-5- oxopyrrolidin-3-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 443.2 622

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methyl-1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 478.2 623

5-(2-((2,2-dimethyl-1,1- dioxidotetrahydro-2H- thiopyran-4-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 492.2 624

5-(2-((8,8-dioxido-8- thiabicyclo[3.2.1]ctan-3-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 490.2 625

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2- methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 483.2 626

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((2-oxo-1,2,3,4-tetrahdyroquinolin- 4-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 477.2 627

(R)-N-(2-chloro-5- methylpyridin-4-yl)-1,2,4-trimethyl-5-(2-oxo-2-((1,1,1- trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3- carboxamide 445.1 628

N-(2-chloro-6-methylpyridin- 4-yl)-5-(2-(((1s,4s)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 447.2 629

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-(((1s,4s)-4-(prop-2-yn-1- yloxy)cyclohexxyl)amino)acetyl)-1H-pyrrole-3-carboxamide 468.3 630

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(3-(pyridin-4-yl)-1,2,4- oxadiazol-5- yl)cyclohexyl)amino)acetyl)-1H-pyrrole-3-carboxamide 559.2 631

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(3-(pyrazin-2-yl)-1,2,4- oxadiazol-5- yl)cyclohexyl)amino)acetyl)-1H-pyrrole-3-carboxamide 560.1 632

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-(5-methyl-1,2,4-oxadiazol-3- yl)cyclohexyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 496.2 633

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(thiophen-2- yl)cyclohexyl)amino)acetyl)- 1H-pyrrole-3-carboxamide 496.2634

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(5-thiophen-2-yl)-1,2,4- oxadiazol-3- yl)cyclohexyl)amino)acetyl)-1H-pyrrole-3-carboxamide 564.2 635

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimetthyl-5-(2-((1-(4-methylthiazol-2- yl)cyclopentyl)amino)-2- oxoacetyl)-1H-pyrrole-3-carboxamide 497.2 636

5-(2-((1-(1H-tetrazol-5- yl)cyclopentyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 468.2 637

5-(2-((1-(5-cyclopropyl-1,2,4- oxadiazol-3- yl)cyclopentyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimetthyl-1H-pyrrole-3-carboxamide 508.1 638

N-(2-chloro-6-methylpyridin- 4-yl)-1,2,4-trimethyl-5-(2-oxo- 2-((4-(trifluoromethyl)etetrahydro- 2H-pyran-4-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 501.2 639

(R)-5-(2-((1-acetylpiperidin-3- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 457.2640

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl- 5-((2-((1-(methylsulfonyl)piperidin-3- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 493.2 641

(S)-5-(2-((1-acetylpiperidin-3- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 457.2642

(S)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl- 5-(2-((1-(methylsulfonyl)piperidin-3- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 493.2 643

5-(2-(((1R,5S,6s)-3-acetyl-3- azabicyclo[3.1.0]hexan-6-yl)amino)-2-oxoacetyl)-N-(4- fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 455.2 644

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2- (((1R,5S,6s)-3-(methylsulfonyl)-3- aabicyclo[3.1.0]hexan-6- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 491.2 645

5-(2-((1-acetyl-3- methylazetidin-3-yl)amno)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 443.2 646

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((2-(thiophen-3- yl)ethyl)amino)acetyl)-1H- pyrrole-3-carboxamide 442.2 647

N-(4-fluoro-3-methylphenyl)- 5-(2-((2-hydroxy-2-(thiophen-2-yl)propyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 472.2 648

N-(4-fluoro-3-methylphenyl)- 5-(2-((2-hydroxy-22-(thiophen-3-yl)ethyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 458.2 649

5-(2-((2-(2,4-dioxothiazolidin- 3-yl)ethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 475.1 650

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2-(5-methyl-3-oxo-2,3-dihdyro-1H- pyrazol-4-yl)ethyl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 456.2 651

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((2-methyl-1-(4-methylpiperazin- 1-yl)propan-2-yl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 486.3 652

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-(oxetan-3-yl)piperidin-4- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 471.3 653

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(tetrahydro-2H-pyran-4- yl)piperidin-4- yl)mino)acetyl)-1H-pyrrole-3-carboxamide 499.3 654

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(tetrahydro-2H-thiopyran-4- yl)piperidin-4-yl)amino)acetyl)-1H-pyrrole-3- carboxamide 515.3 655

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-thiophen-2-yl)piperidin-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide497.3 656

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(thiaol-2-yl)piperidin-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide498.2 657

N-(44-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(pyridin-2-yl)piperidin-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide4922.3 658

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(pyrimidin-2-yl)piperidin-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide493.3 659

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(pyrazin-2-yl)piperidin-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide493.3 660

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(pyridazin-3-yl)piperidin-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide493.3 661

5-(2-((1-((4-(4- chlorophenyl)piperazin-1- yl)methyl)cyclopropyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 580.3 662

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(pyridin-4-yl)piperidin-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide492.3 663

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-((1-(pyridin-3-yl)piperidin-4- yl)amino)acetyl)-1H-pyrrole-3- carboxamide492.3 664

(R)-5-(2-((1-acetylpyrrolidin-3- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 443.2665

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl- 5-(2-((1-(methylsulfonyl)pyrrolidin-3- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 479.2 666

(S)-5-(2-((1-acetylpyrrolidin-3- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 443.2667

(S)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl- 5-(2-((1-(methylsulfonyl)pyrrolidin-3- yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 479.2 668

5-(2-(((1s,3s)-3- acetamidocyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 443.2 669

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-(((1s,3s)- 3-(methylsulfonamido)cyclobutyl) amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 479.2 670

5-(2-(((1r,3r)-3- acetamidocyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 443.2 671

(S)-N-(4-fluoro-3- emthylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-((2-oxopyrroldin- 3-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 415.2 672

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-((2-oxopyrrolidin- 3-yl)amino)acetyl)-1H-pyrole-3-carboxamide 415.2 673

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-((2-oxopiperidin-3- yl)amino)acetyl)-1H-pyrrole-3-carboxamide 429.2 674

5-(2-((6-fluoro-2-oxo-1,2- dihydropyridin-4-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 443.2 675

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl) amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 444.2 676

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1s,4s)-4-(hydroxymethyl)cyclohexyl) amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 444.2 677

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1r,4r)-4-(2- hydroxypropan-2-yl)cyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 472.2 678

N-(4-fluoro-3-methylphenyl)- 5-(2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol- 5-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 464.2 679

5-(2-((4,4-dimethyl-2- oxopyrrolidin-3-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 443.2 680

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((7- methyl-6-oxo-5-azaspiro[2.4]heptan-7- yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide455.2 681

N-(4-fluoro-3-methylphenyl)- 5-(2-((4-((1-hydroxy-2- methylpropan-2-yl)carbamoyl)tetrahydro-2H- pyran-4-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 531.3 682

(S)-5-(2-((4-(sec- butylcarbamoyl)tetrahydro-2H- pyran-4-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 515.3 683

N-(4-fluoro-3-methylphenyl)- 5-(2-((4-(((1s,3s)-3-hydroxy-1-methylcyclobutyl)carbamoyl) tetrahydro-2H-pyran-4-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 543.3684

(R)-N-(3-chloro-5- methylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-((5-oxopyrrolidin- 3-yl)amino)acetyl)-1H-pyrrole-3-carboxamide 431.2 685

N-(3-chloro-5-methylphenyl)- 5-(2-(((1s,4s)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 446.2 686

(R)-N-(3-chloro-5- methylphenyl)-1,2,4-trimethyl- 5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide 444.1 687

N-(3-chloro-5-methylphenyl)- 5-(2-(((1r,4r)-4-hydroxy-1-metthylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 460.2 688

N-(3-chloro-5-methylphenyl)- 5-(2-(((1R,3R)-3-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 446.2 689

N-(3-chlorophenyl)-5-(2- (((1R,3R)-3- hydroxycyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 432.2 690

N-(3-(difluoromethyl)phenyl)- 5-(2-(((1s,4s)-4-hydroxycylcohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 448.2 691

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methyl-1-(pyrimidin-2- yl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 507.3 692

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methyl-1-(1-methyl-1H- pyrazole-5-carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide 537.2 693

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methyl-1-(1-methyl-1H- pyrazole-4-carbonyl)piperidin-4-yl)amno)-2-oxoacetyl)-1H- pyrrole-3-carboxamide 537.2 694

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((1-methylcyclohex-3-en-1- yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide426.2 695

N-(4-fluoro-3-methylphenyl)- 5-(2-(((3aS,4R,6S,6aR)-6- hydroxy-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)amino)-2-oxoacetyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 488.2696

1-ethyl-N-(4-fluoro-3- methylphenyl)-5-(2-(((1r,4r)-4- hydroxy-1-methylcyclohexxyl)amino)-2- oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 458.3 697

N-(3-(difluoromethyl)phenyl)- 5-(2-(((1r,4r)-4-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 448.2 698

5-(2-((1-(1H-tetrazol-5- yl)cyclopentyl)amino)-2- oxoacetyl)-N-(3,4-difluorophenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxmide 472.1 699

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-mmethyl-1-(thiazol-2- yl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 612.3 700

N-(3-(difluoromethyl)phenyl)- 5-(2-(((1r,4r)-4-hydroxy-1-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-rimethyl-1H-pyrrole-3-carboxamide 462.2 701

N-(3-(difluoromethyl)phenyl)- 5-(2-(((1s,4s)-4-hydroxy-1-methylcyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 462.2 702

5-(2-(((3S,4R)-3,4-dihydroxy- 1-methylcyclohexyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 460.2 703

5-(2-(((3R,4S)-3,4-dihydroxy- 1-methylcyclohexyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 460.2. 704

N-(3-(difluoromethyl)phenyl)- 5-(2-(((1R,3R)-3-hydroxycyclohexyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 448.2 705

N-(3-(difluoromethyl)phenyl)- 5-(2-(((1s,3s)-3-hydroxy-1-methylcyclobutyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 434.2 706

N-(3,4-difluorophenyl)-5-(2- (((1r,4r)-4-hydroxy-1-methylcyclohexxyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxmaide 448.2 707

N-(3,4-difluorophenyl)-4-(2- (4-((4-fluoro-3- methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2- yl)-2-oxoacetamido)-4- methylpiperidine-1-carboxamide 584.2 708

5-(2-((1-(3-(difluoromethyl)-1- methyl-1H-pyrazole-4-carbonyl)-4-methylpiperidin-4- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 587.3709

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methyl-1-(1H-pyrazole-4- carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide 523.2 710

(R)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl- 5-(2-oxo-2-((4-oxo-5-azaspiro[2.4]heptan-7- yl)amino)acetyl)-1H-pyrrole-3- carboxamide 441.2711

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-(((3R,4R)-4-morpholinotetrahydrofuran- 3-yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide 487.2 712

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-oxo-2-(((1R,2S,3R,4S)-2,3,4- trihydroxycyclopentyl)amino)acetyl)-1H-pyrrole-3- carboxamide 448.2 713

5-(2-(((4R,5S)-4,5- dihydroxycycloheptyl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 460.2 714

5-(2-((1,4-dioxepan-6- yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4- trimethyl-1H-pyrrole-3- carboxamide 432.1715

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methyl-1-(pyrazin-2- yl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 507.3 716

5-(2-((1-cyclopropyl-1-(5- methyl-1,2,4-oxadiazol-3-yl)ethyl)amino)-2-oxoacetyl)- N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3- carboxamide 482.2 717

N-(4-fluoro-3-methylphenyl)- 12,4-trimethyl-5-(2-((4-methyl-1-(pyrimidin-4- yl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 507.3 718

5-(2-((1-(difluoromethoxy)-2- methylpropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3- methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 454.2 719

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methyl-1-(pyrazolo[1,5- a]pyrimidine-3- carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H- pyrrole-3-carboxamide 574.3 720

N-(3-(difluoromethyl)phenyl)- 5-(2-(((1r,3r)-3-hydroxy-1-methylcycloutyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 434.2 721

N-(3-(difluoromethyl)phenyl)- 5-(2-(((1R,3R)-3-hydroxycyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 434.2 722

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1S,3R)-3-hydroxy-1-methylcyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 430.2 723

N-(4-fluoro-3-methylphenyl)- 5-(2-(((1S,3S)-3-hydroxy-1-methylcyclopentyl)amino)-2- oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide 430.2 724

N-(4-fluorophenyl)-5-(2- (((1s,4s)-4- hydroxycyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 416.2 725

(R)-N-(4-fluorophenyl)-1,2,4- trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide 414.2 726

N-(5-chloropyridin-3-yl)-5-(2- (((1s,4s)-4- hydroxycyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H- pyrrole-3-carboxamide 433.2 727

(R)-N-(5-chloropyridin-3-yl)- 1,2,,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-1H-pyrrole-3- carboxamide431.1 728

N-(4-fluoro-3-methylphenyl)- 1,2,4-trimethyl-5-(2-((4-methyl-1-(pyridazin-3- yl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-pyrrole-3- carboxamide 507.3 729

(S)-3-(2-(sec-butylamino)-2- oxoacetyl)-2-chloro-N-(6-fluoro-5-methylpyridin-3-yl)- 5,6,7,8-tetrahydroindolizine-1-carboxamide 435.1 730

2-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-3-(2-oxo-2-((1,1,1-trifluoro-2- methylpropan-2- yl)amino)acetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 489.0 731

(S)-2-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-3-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino)acetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 475.1 732

(R)-2-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-3-(2-oxo-2-((1,1,1-trifluoropropan-2- yl)amino0acetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 475.1 733

(S)-5-(2-(sec-butylamino)-2- oxoacetyl)-6-chloro-N-(6-fluoro-5-methylpyridin-3-yl)- 2,3-dihydro-1H-pyrrolizine-7- carboxamide421.0 734

5-(2-(((2-aminothiazol-5- yl)methyl)amino)-2- oxoacetyl)-6-chloro-N-(6-fluoro-5-methylpyridin-3-yl)- 2,3-dihydro-1H-pyrrolizine-7- carboxamide477.0 735

(R)-6-chloro-N-(6-fluoro-5- methylpyridin-3-yl)-5-(2-((1-(3-methyl-1,2,4-oxxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 475.1 736

(S)-6-chloro-N-(6-luoro-5- methylpyridin-3-yl)-5-(2-((1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7- carboxamide 475.1 737

N-(4-fluoro-3-methylphenyl)- 3-(2-(((1s,4s)-4-hydroxy-1-methylcyclohexyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 470.2 738

(4-(2-(1-((3,4- difluorophenyl)carbamoyl)-2- methyl-5,6,7,8-tetrahdyroindolizin-3-yl)-2- oxoacetamido)phenyl)boronic acid 482.1 739

N-(4-fluoro-3-methylphenyl)- 2-methyl-3-(2-oxo-2-(pyridin-3-ylamino)acetyl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 435.1 740

N-(4-fluoro-3-methylphenyl)- 3-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 470.2 741

3-(2-((2-aminoethyl)amino)-2- oxoacetyl)-N-(3,4-difluorophenyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1- carboxamide405.1 742

N-(3,4-difluorophenyl)-2- methyl-3-92-((4-methylpiperidin-4-yl)amino)-2- oxoacetyl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 459.2 743

3-(22-((1-(2H-tetrazol-5- yl)cyclopentyl)amino)-2- oxoacetyl)-N-(3,4-difluorophenyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1- carboxamide498.2 744

N-(3,3-difluorocyclopentyl)-3- (2-((1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-2-methyl- 5,6,7,8-tetrahdyroindolizine-1-carboxamide 438.3 745

3-(2-((1- (hydroxymethyl)cyclobutyl)amino)- 2-oxoacetyl)-2-methyl-N-(1-methylcyclopentyl)-5,6,7,8- tetrahdyroindolizine-1- carboxamide 416.3746

N-cyclopentyl-3-(2-((1- (hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-2-methyl- 5,6,7,8-tetrahydroindolizine-1-carboxamide 402.3 748

3-(2-((1- (hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)- 5,6,7,8-tetrahydroindolizine-1- carboxamide414.2 749

3-(2-((1- (hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-2-methyl-N-(5-(trifluoromethyl)thiazol-2- yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide 485.1 750

3-(2-((1- (hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-2-methyl-N-(5-methylthiazol-2-yl)-5,6,7,8- tetrahydroindolizine-1- carboxamide431.2 751

3-(2-((1- (hydroxymethyl)cyclobutyl) amino)-2-oxoacetyl)-2-methyl-N-(thiazol-2-yl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 417.2 752

N-(3,3-difluorocyclopentyl)-3- (2-((1-hydroxy-2-methylpropan-2-yl)amino)-2- oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1- carboxamide 426.2 753

3-(2-((1-hydroxy-2- methylpropan-2-yl)amino)-2-oxoacetyl)-2-methyl-N-(1- methylcyclopentyl)-5,6,7,8-tetrahydroindolizine-1- carboamide 404.3 754

N-cyclopentyl-3-(2-((1- hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-2- methyl-5,6,7,8- tetrahydroindolizine-1-carboxamide 390.2 756

3-(2-((1-hydroxy-2- methylpropan-2-yl)amino)-2-oxoacetyl)-2-methyl-N-(1- methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 402.2 757

3-(2-((1-hydroxy-2- methylpropan-2-yl)amino)-2-oxoacetyl)-2-methyl-N-(5- (trifluoromethyl)thiazol-2-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide 473.2 758

3-(2-((1-hydroxy-2- methylpropan-2-yl)amino)-2-oxoacetyl)-2-methyl-N-(5- methylthiazol-2-yl)-5,6,7,8-tetrahydroindazoline-1- carboxamide 419.2 759

3-(2-((1-hydroxy-2- methylpropan-2-yl)amino)-2- oxoacetyl)-2-methyl-N-(thiazol-2-yl)-5,6,7,8- tetrahydroindolizine-1- carboxamide 405.1Further Forms of Compounds Disclosed HereinIsomers/Stereoisomers

In some embodiments, the compounds described herein exist as geometricisomers. In some embodiments, the compounds described herein possess oneor more double bonds. The compounds presented herein include all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as thecorresponding mixtures thereof. In some situations, the compoundsdescribed herein possess one or more chiral centers and each centerexists in the R configuration, or S configuration. The compoundsdescribed herein include all diastereomeric, enantiomeric, and epimericforms as well as the corresponding mixtures thereof. In additionalembodiments of the compounds and methods provided herein, mixtures ofenantiomers and/or diastereoisomers, resulting from a single preparativestep, combination, or interconversion are useful for the applicationsdescribed herein. In some embodiments, the compounds described hereinare prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred. In some embodiments, thediastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and are separated bytaking advantage of these dissimilarities. In some embodiments, thediastereomers are separated by chiral chromatography, or preferably, byseparation/resolution techniques based upon differences in solubility.In some embodiments, the optically pure enantiomer is then recovered,along with the resolving agent, by any practical means that would notresult in racemization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds disclosed herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and thepharmaceutically acceptable salts, solvates, or stereoisomers thereofwhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i.e., ³H and carbon-14,i.e., ¹⁴C, isotopes are particularly preferred for their ease ofpreparation and detectability. Further, substitution with heavy isotopessuch as deuterium, i.e., ²H, produces certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds disclosed herein, or a solvate, or stereoisomer thereof, or byseparately reacting a purified compound in its free form with a suitableacid or base, and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineral,organic acid or inorganic base, such salts including, acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylateundeconate and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid and muconic acid. In some embodiments, other acids,such as oxalic, while not in themselves pharmaceutically acceptable, areemployed in the preparation of salts useful as intermediates inobtaining the compounds disclosed herein, solvate, or stereoisomerthereof and their pharmaceutically acceptable acid addition salts.

In some embodiments, those compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metalcation, with ammonia, or with a pharmaceutically acceptable organicprimary, secondary, tertiary, or quaternary amine. Representative saltsinclude the alkali or alkaline earth salts, like lithium, sodium,potassium, calcium, and magnesium, and aluminum salts and the like.Illustrative examples of bases include sodium hydroxide, potassiumhydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄ alkyl)₄, and thelike.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like. It should be understood thatthe compounds described herein also include the quaternization of anybasic nitrogen-containing groups they contain. In some embodiments,water or oil-soluble or dispersible products are obtained by suchquaternization.

Solvates

In some embodiments, the compounds described herein exist as solvates.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein can be conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein can be conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran ormethanol. In addition, the compounds provided herein can exist inunsolvated as well as solvated forms. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thecompounds and methods provided herein.

Tautomers

In some situations, compounds exist as tautomers. The compoundsdescribed herein include all possible tautomers within the formulasdescribed herein. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH.

Preparation of Compounds Example 1: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis ofN-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrrole-3-carboxamide (1c)

HATU (3.4 g, 8.8 mmol) was added to a solution of1-methyl-1H-pyrrole-3-carboxylic acid (1a, 1 g, 8 mmol) in DMA (15 mL)at rt. After 30 min, 4-fluoro-3-methylaniline (1b, 1 g, 8 mmol) andDIPEA (1 g, 8 mmol) in DMA (5 mL) were added dropwise. The resultingmixture was stirred at rt for 20 hrs. The reaction mixture was dilutedwith EtOAc, washed with aqueous HCl (0.5 N, 20 mL) and brine. Theorganic layer was dried over Na₂SO₄, filtered, concentrated in vacuo,and purified by flash chromatography on silica gel (EtOAc/Hexanes0˜100%) to afford the product as white solid (0.9 g). ESI-MS, m/z 233(MH)⁺.

Step 2: Synthesis of ethyl2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)-2-oxoacetate(1e)

Ethyl 2-chloro-2-oxoacetate (1d, 0.6 g, 4.4 mmol) was added to asolution of 1c (0.5 g, 2.2 mmol) in DCM (10 mL) at 0° C. under argon.After 20 min, AlCl₃ (0.6 g, 4.4 mmol) was added in portions, and themixture was warmed to rt for 4 hrs. The reaction mixture was poured overice-water, and extracted with DCM (2×30 mL). The combined extracts werewashed with water, saturated NaHCO₃, brine and concentrated under vacuumto give crude product 1e. ESI-MS, m/z 333 (MH)⁺.

Step 3: Synthesis of2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)-2-oxoaceticacid (1g)

NaOH (2 N, 3 mL) was added to a solution of the crude product 1e in EtOH(6 mL) at 0° C. The mixture was warmed to rt for 2 hrs, then, cooledwith ice-water and carefully neutralized with aqueous HCl (0.5 N) topH˜2. The resulting mixture was concentrated under vacuum to removeMeOH, then, lyophilized to afford crude product 1g as white solid:ESI-MS, m/z 305 (MH)⁺.

Step 4: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrrole-3-carboxamide(1)

HATU (90 mg, 0.24 mmol) was added to a solution of 1g (60 mg, 0.19) inDMA (0.75 mL) at 0° C. After 20 min, tert-butylamine (20 mg, 0.28) andDIPEA (50 mg, 0.38 mmol) in DMA (0.4 mL) were added. The reactionmixture was stirred at rt for 20 hrs. The reaction mixture was quenchedwith aqueous TFA (4%, 0.4 mL), then, extracted with EtOAc (10 mL). Theorganic layer was washed with water and brine, concentrated in vacuo,then, purified by reverse phase chromatography eluted with ACN andwater, and dried using lyophilization to afford the title product aswhite solid. ESI-MS, m/z 360 (MH)⁺.

Example 2: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis of ethyl 1,2,4-trimethyl-1H-pyrrole-3-carboxylate (2b)

MeI (0.75 g, 5.3 mmol) was added to a mixture of 2a (0.5 g, 3.2 mmol)and K₂CO₃ (1 g, 7.2 mmol) in DMA (15 mL) at 0° C. The reaction mixturewas warmed to rt for 40 hrs. The reaction mixture was diluted with theaddition of water, and extracted with EtOAc (2×10 mL). The combinedextracts were washed with water and brine, concentrated in vacuo, then,purified by flash chromatography on silica gel (EtOAc/Hexanes 0˜100%) toafford 2b as white solid (0.3 g). ESI-MS, m/z 182 (MH)⁺.

Step 2: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide(2c)

LiHMDS (1 N in THF, 4 mL) was added to a solution of 2b (0.3 g, 1.7mmol) and 1b (0.3 g, 2.4 mmol) in THF (10 mL) at 0° C. under argon.After 1 h, the reaction was quenched with saturated aqueous NH₄Cl andextracted with EtOAc. The organic layer was washed with brine andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (EtOAc/Hexanes 0˜100%) to afford 3b as white solid (0.35g). ESI-MS, m/z 261 (MH)⁺.

Step 3: Synthesis of ethyl2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetate(2d)

The title compound was prepared following the procedures described inExample 1, Steps 2, using 2c. The final product was purified by flashchromatography on silica gel (EtOAc/Hexanes 0˜100%) to afford 2d aswhite solid (0.32 g). ESI-MS, m/z 361 (MH)⁺.

Step 4: Synthesis of2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoaceticacid (2e)

The title compound was prepared following the procedures described inExample 1, Steps 3, using 2d instead of 1d. The crude product was driedusing lyophilization as white solid, which was used without furtherpurification. ESI-MS, m/z 333 (MH)⁺.

Step 5: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 1, Step 4, using 2e. The final product was purified by reversephase chromatography eluted with ACN and water and dried usinglyophilization to afford the title products as white solids. ESI-MS, m/z388 (MH)⁺.

Example 3: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

The title compound was prepared from compound 2a following the proceduredescribed in Example 2, Step 2 through Step 5, using4-fluoro-3-chloroaniline instead of 4-fluoro-3-methylaniline. The finalproduct was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title product aswhite solid. ESI-MS, m/z 394 (MH)⁺.

Example 4: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compound was prepared following the procedure described inExample 2, Step 2 through Step 5, using 3,4-difluoroaniline instead of4-fluoro-3-methylaniline. The final product was purified by reversephase chromatography eluted with ACN and water and dried usinglyophilization to afford the title product as a white solids. ESI-MS,m/z 392 (MH)⁺.

Example 5: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(6-fluoropyridin-3-yl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 2 through Step 5, using 6-fluoropyridin-3-amine insteadof 4-fluoro-3-methylaniline. The final product was purified by reversephase chromatography eluted with ACN and water and dried usinglyophilization to afford the title products as white solids. ESI-MS, m/z375 (MH)⁺.

Example 6: Synthesis of5-(2-((1-fluoro-2-methylpropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 1-fluoro-2-methylpropan-2-amine. The finalproduct was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title products aswhite solids. ESI-MS, m/z 406 (MH)⁺.

Example 7: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((1-(hydroxymethyl)cyclopropyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using (1-aminocyclopropyl)methanol. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 402 (MH)⁺.

Example 8: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 2-amino-2-methylpropan-1-ol. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ¹H NMR (400 MHz, CD₃OD) δ 8.2 (s, 1H), 7.42-7.49 (m, 2H), 6.99(dd, 1H, J=8.7, 9.3 Hz), 3.81 (s, 3H), 3.64 (s, 2H), 2.36-2.38 (m, 6H),2.26 (s, 3H), 1.38 (s, 6H). ESI-MS, m/z 404 (MH)⁺.

Example 9: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 1,1,1-trifluoro-2-methylpropan-2-amine. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 442 (MH)⁺.

Example 10: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 1,1,1-trifluoropropan-2-amine. The finalproduct was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title products aswhite solids. ESI-MS, m/z 428 (MH)⁺.

Example 11: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((4-hydroxy-2-methylbutan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 3-amino-3-methylbutan-1-ol. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 418 (MH)⁺.

Example 12: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((1-(hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using (1-aminocyclobutyl)methanol. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 416 (MH)⁺.

Example 13: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((3-(hydroxymethyl)tetrahydrofuran-3-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compound was prepared following the procedure described inExample 2, Step 5, using (3-aminotetrahydrofuran-3-yl)methanol. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 432 (MH)⁺.

Example 14: Synthesis of5-(2-(((3s,5s,7s)-adamantan-1-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 1-adamantylamine. The final product waspurified by reverse phase chromatography eluted with ACN and water anddried using lyophilization to afford the title products as white solids.ESI-MS, m/z 466 (MH)⁺.

Example 15: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 3-aminoadamantan-1-ol. The final product waspurified by reverse phase chromatography eluted with ACN and water anddried using lyophilization to afford the title products as white solids.ESI-MS, m/z 482 (MH)⁺.

Example 16: Synthesis ofN-(6-fluoropyridin-3-yl)-5-(2-(((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 5, using 3-aminoadamantan-1-ol instead of tert-butylamine. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 469 (MH)⁺.

Example 17: Synthesis of5-(2-(((1r,3r)-adamantan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 2-adamantylamine. The final product waspurified by reverse phase chromatography eluted with ACN and water anddried using lyophilization to afford the title products as white solids.ESI-MS, m/z 466 (MH)⁺.

Example 18: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(((2R,3as,5S,6as)-hexahydro-2,5-methanopentalen-3a(1H)-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 3-noradamantanamine. The final product waspurified by reverse phase chromatography eluted with ACN and water anddried using lyophilization to afford the title products as white solids.ESI-MS, m/z 452 (MH)⁺.

Example 19: Synthesis ofN-(6-fluoropyridin-3-yl)-5-(2-(((2R,3as,5S,6as)-hexahydro-2,5-methanopentalen-3a(1H)-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 5, using 3-noradamantanamine instead of tert-butylamine. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 439 (MH)⁺.

Example 20: Synthesis of5-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine.The final product was purified by reverse phase chromatography elutedwith ACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 484 (MH)⁺.

Example 21: Synthesis of5-(2-(tert-butoxyamino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxamide

The title compound was prepared following the procedure described inExample 1, 4-fluoro-3-chloroaniline instead of 4-fluoro-3-methylanilinein Step 1, and using O-(tert-butyl)hydroxylamine instead oft-butylaminein Step 5. The final product was purified by reverse phasechromatography eluted with ACN and water and dried using lyophilizationto afford the title products as white solids. ESI-MS, m/z 396 (MH)⁺.

Example 22: Synthesis of tert-butyl2-(2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetamido)-2-methylpropanoate

The title compound was prepared following the procedure described inExample 2, Step 5, using tert-butyl 2-amino-2-methylpropanoate. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 474 (MH)⁺.

Example 27: Synthesis of methyl(2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetyl)-L-threoninate

DIPEA (0.229 g, 1.77 mmol) was added to a mixture of 2e (0.195 g, 0.59mmol), L-Threonine methyl ester hydrochloride (0.11 g, 0.65 mmol) andHATU (0.269 g, 0.71 mmol) in DMF (3 mL) at ambient temperature. After 16h, the reaction mixture was diluted into aqueous HCl (1 N, 20 mL) andextracted with EtOAc (3×15 mL). The combined extracts were washed withaqueous HCl (1 N, 10 mL), aqueous NH₄Cl (saturated, 10 mL) and brine (10mL). The organic layer was dried over Na₂SO₄ (s), filtered, concentratedin vacuo, then, purified by flash chromatography on silica gel(EtOAc/Hexanes 0˜100%) to afford the title product as white solid (0.223g). ESI-MS, m/z 448.2 (MH)⁺.

Example 29: Synthesis of2-(2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetamido)-2-methylpropanoicacid

TFA (0.4 mL) was added to a solution of Example 22 (15 mg) in DCM (1 mL)at 0° C. After 2 hrs at 0° C., the reaction mixture was warmed to rt for1 hr. The solvent was removed and the residue was purified by reversephase chromatography eluted with ACN and water and dried usinglyophilization to afford the title products as white solids. ESI-MS, m/z418 (MH)⁺.

Example 34: Synthesis of(2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetyl)-L-threonine

NaOH (1 N, 0.5 mL) was added to a solution of Example 27 (0.093 g, 0.208mmol) in MeOH (5 mL) at ambient temperature. After 2 h the reactionmixture was carefully neutralized with aqueous HCl (1 N) to pH˜2. Theresulting mixture was concentrated under vacuum to remove MeOH, then,purified by reverse phase chromatography eluted with ACN and water, anddried using lyophilization to afford the title product as pale yellowsolid: ESI-MS, m/z 434.2 (MH)⁺.

Example 36: Synthesis of5-(2-((1-amino-2-methyl-1-oxopropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 2-amino-2-methylpropanamide. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 417 (MH)⁺.

Example 37: Synthesis of5-(2-((1-carbamoylcyclopropyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 1-aminocyclopropane-1-carboxamide. The finalproduct was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title products aswhite solids. ESI-MS, m/z 415 (MH)⁺.

Example 38: Synthesis of5-(2-((1-carbamoylcyclopentyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 1-aminocyclopentane-1-carboxamide. The finalproduct was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title products aswhite solids. ESI-MS, m/z 443 (MH)⁺.

Example 42:5-(2-(((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

DIPEA (0.25 g, 1.93 mmol) and DMAP (0.02 g, 0.16 mmol) were added to amixture of 34 (0.7 g, 0.16 mmol), NH₄Cl (0.043 g, 0.81 mmol) and HATU(0.184 g, 0.48 mmol) in DMF (3 mL) at ambient temperature. After 16 h,the reaction mixture was diluted into aqueous HCl (1 N, 20 mL) andextracted with EtOAc (3×15 mL). The combined extracts were washed withaqueous HCl (1 N, 10 mL), aqueous NH₄Cl (saturated, 10 mL) and brine (10mL). The organic layer was dried over Na₂SO₄ (s), filtered, concentratedin vacuo. The final product was purified by reverse phase chromatographyeluted with ACN and water and dried using lyophilization to afford thetitle products as white solids. ESI-MS, m/z 433.2 (MH)⁺.

Example 43: Synthesis of5-(2-(((1r,3r,5r,7r)-2-carbamoyladamantan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 2-aminoadamantane-2-carboxamide. The finalproduct was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title products aswhite solids. ESI-MS, m/z 509 (MH)⁺.

Example 47: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(4-hydroxypiperidin-1-yl)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using piperidin-4-ol. The final product was purifiedby reverse phase chromatography eluted with ACN and water and driedusing lyophilization to afford the title products as white solids.ESI-MS, m/z 416 (MH)⁺.

Example 48: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((1R,3s,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using (1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-ol. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 442 (MH)⁺.

Example 49: Synthesis of5-(2-(2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine. The final product waspurified by reverse phase chromatography eluted with ACN and water anddried using lyophilization to afford the title products as white solids.ESI-MS, m/z 434 (MH)⁺.

Example 50:N-(4-fluoro-3-methylphenyl)-5-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-1-(2-hydroxyethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 71, Step 5, using 2-amino-2-methylpropan-1-ol. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 434 (MH)⁺.

Example 53: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(4-hydroxy-3,3-dimethylpiperidin-1-yl)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 3,3-dimethylpiperidin-4-ol. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 444.2 (MH)⁺.

Example 59:N-(4-fluoro-3-methylphenyl)-5-(2-(((1s,3R,4s,5S,7s)-4-hydroxyadamantan-1-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 5-aminoadamantan-2-ol. The final product waspurified by reverse phase chromatography eluted with ACN and water anddried using lyophilization to afford the title products as white solids.ESI-MS, m/z 482 (MH)⁺.

Example 63: Synthesis of(R)-5-(2-((3,3-dimethylbutan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using (R)-(−)-3,3-dimethyl-2-butylamine. The finalproduct was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title products aswhite solids. ESI-MS, m/z 416.2 (MH)⁺.

Example 64: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-(neopentylamino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 2,2-dimethylpropan-1-amine. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 402.2 (MH)⁺.

Example 65: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((3-hydroxy-2,2-dimethylpropyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 3-amino-2,2-dimethylpropan-1-ol. The finalproduct was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title products aswhite solids. ESI-MS, m/z 418.2 (MH)⁺.

Example 66: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis of ethyl 1,2,4-trimethyl-1H-pyrrole-3-carboxylate(66b)

MeI (31.8 g, 224.3 mmol) was added to a mixture of 66a (25 g, 149.5mmol) and KOH (16.8 g, 299 mmol) in DMSO (250 mL) at 0° C. The reactionmixture was warmed to rt for 16 hrs. The reaction mixture was extractedwith 4× Et₂O. The combined extracts were washed with water and brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford thetitle compound 66b as brown solid (24.6 g, 91%) which was used withoutfurther purification. ESI-MS, m/z 182 (MH)⁺.

Step 2: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide(66c)

LiHMDS (272 mL, 1 N in THF) was added dropwise over 45 min to a solutionof 66b (24.6 g, 135.73 mmol) and 3-methyl-4-fluoroaniline (18.83 g,149.3 mmol) in THF (270 mL) at 0° C. The reaction mixture was allowed towarm slowly to ambient temperature. After 16 h the reaction mixture wasquenched with NH₄Cl (sat) and water. The layers were separated and theaqueous was extracted 3× EtOAc. The combined organics were washed withNH₄Cl (sat) and brine, dried over Na₂SO₄, filtered and concentrated. Thecrude residue was suspended in 1:1 EtOAc/hexanes and stirred for 1 h at40° C., then cooled to ambient temperature and filtered. The filter cakewas washed with hexanes and dried to afford the title compound 66c astan solid (31.85 g, 90%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 7.58(d, J=7.2 Hz, 1H), 7.45 (m, 1H), 7.02 (t, J=9.6 Hz, 1H), 6.44 (s, 1H),3.43 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H). ESI-MS, m/z 261(MH)⁺.

Step 3: Synthesis of ethyl2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetate(66d)

To a solution of 66c (31.85 g, 121.89 mmol) in DCM (500 mL) at 0° C. wasadded ethyl chlorooxoacetate (24.96 g, 182.84 mmol) dropwise over 30mins and the reaction mixture was allowed to warm slowly to ambienttemperature. After 16 h the reaction mixture was washed with H₂O andNaHCO₃ (sat) and then concentrated in vacuo to afford the title compound66d (44 g, quant) as a brown solid which was used without any furtherpurification. ESI-MS, m/z 361 (MH)⁺.

Step 4: Synthesis of2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoaceticacid (66e)

To a solution of 66d (43.9 g, 121.89 mmol) in THF (200 mL) and MeOH (200mL) was added 1N NaOH (300 mL). After 15 min the reaction mixture waspartially concentrated to remove organics, diluted with EtOAc andpartially concentrated again. The heterogeneous mixture was diluted withwater and washed 4× EtOAc. The heterogeneous aqueous was acidified withconc. HCl to pH=1 and extracted with 4× EtOAc. The heterogeneous organiclayer was washed with brine, filtered and the filter cake was washedwith hexanes. The crude solids were suspended in EtOAc (200 mL) andhexanes (200 mL) and stirred for 1 h at 45° C., then cooled to ambienttemperature, filtered and washed with hexanes. The solids were furtherdried in vacuo to provide the title compound 66e (34.21 g, 84%) as anoff-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.96 (s, 1H), 7.60 (d,J=6.9 Hz, 1H), 7.46 (m, 1H), 7.07 (t, J=9.6 Hz, 1H), 3.78 (s, 3H), 2.32(s, 3H), 2.23 (s, 3H), 2.20 (s, 3H). ESI-MS, m/z 333 (MH)⁺.

Step 5: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

To a solution of 66e (20 g, 60.18 mmol), 1-amino-2-methylpropan-2-ol(5.9 g, 66.20 mmol)) and HATU (27.46 g, 72.22 mmol) in DMF (200 mL) atambient temperature was added DIPEA (23.3 g, 180.54 mmol). After 2 h thereaction mixture was diluted with 1N HCl and extracted 4× EtOAc. Thecombined organics were washed sequentially with 1 N HCl, NaHCO₃ (sat),and brine, then dried over Na₂SO₄, filtered and concentrated. The crudesolids were suspended in MeCN (100 mL) and water (100 mL) and stirred at40° C. After 1 h the mixture was cooled to ambient temperature andfiltered. The filter cake was washed with 1:1 MeCN/water and dried invacuo. The resultant tan solids were slurried in MeCN (60 mL) andstirred at 45° C. After 1 h the mixture was cooled to ambienttemperature, filtered and washed with cold MeCN. The resultant solidswere dried in vacuo to provide the title compound (17.5 g, 72%) as anoff white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.90 (s, 1H), 8.51 (t,J=5.1 Hz, 1H), 7.60 (d, J=6.9 Hz, 1H), 7.45 (t, J=3 Hz, 1H), 7.06 (t,J=9.3 Hz, 1H), 4.50 (s, 1H), 3.74 (s, 3H), 3.14 (d, J=5.7 Hz, 2H), 2.31(s, 3H), 2.19 (m, 6H), 1.10 (m, 1H). ESI-MS, m/z 404.2 (MH)⁺.

Example 67: Synthesis of(S)—N-(4-fluoro-3-methylphenyl)-5-(2-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using L-tert-leucinol. The final product was purifiedby reverse phase chromatography eluted with ACN and water and driedusing lyophilization to afford the title products as white solids.ESI-MS, m/z 432.2 (MH)⁺.

Example 70: Synthesis of5-(2-(tert-butoxyamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using O-(tert-butyl)hydroxylamine. The final productwas purified by flash chromatography on silica gel eluted with ethylacetate and hexane to afford the title products as pale yellow solids.ESI-MS, m/z 404 (MH)⁺.

Example 71:5-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1-(2-hydroxyethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis of ethyl1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate(71b)

NaH (65% mineral oil, 1 g) was added to a solution of 71a (2 g, 12 mmol)in DMF (100 mL) at 0° C. under argon. After 30 min.,(2-bromoethoxy)(tert-butyl)dimethylsilane (3 g, 12.5 mmol in DMF 10 mL)was added dropwise. The mixture was stirred at 0° C. for 4 hrs. Thereaction was carefully quenched with saturated NH₄Cl at 0° C., then,extracted with EtOAc (3×50 mL). The combined extractions were washedwith water/brine, concentrated in vacuo, and purified by flashchromatography on silica gel (EtOAc/Hexanes 0˜100%) to afford theproduct as brown oil (3 g). ESI-MS, m/z 326 (MH)⁺.

Step 2: Synthesis of1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(4-fluoro-3-methylphenyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(71c)

The title compounds were prepared following the procedure described inExample 2, Step 2. The final product was purified by flashchromatography on silica gel (EtOAc/Hexanes 0˜100%) as brown solid.ESI-MS, m/z 405 (MH)⁺.

Step 3: Synthesis of ethyl2-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((4-fluoro-3-methylphenyl)carbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl)-2,2-difluoroacetate(71d)

A mixture of 71c (0.4 g, 0.99 mmol), K₂CO₃ (0.5 g, 3.6 mmol), Xantphos(0.15 g, 0.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (40 mg)in 1,4-dioxane (5 mL) was flushed with argon, then, ethyl2-bromo-2,2-difluoroacetate (0.5 g) was added under argon. The mixturewas stirred at 100° C. for 20 hrs. After cooling to rt, the reactionmixture was diluted with EtOAc and washed with water/brine, concentratedin vacuo, and purified by flash chromatography on silica gel(EtOAc/Hexanes 0˜40%) to afford the product as brown oil (0.25 g).ESI-MS, m/z 527 (MH)⁺.

Step 4: Synthesis of2-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((4-fluoro-3-methylphenyl)carbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl)-2-oxoaceticacid (71e)

NaOH (2N, 2 mL) was added to a solution of 71d (0.25 g) in MeOH (4 mL)at rt. The mixture was stirred at rt for 2 hrs, then, carefullyneutralized with HCl (0.5 N aqueous) to pH˜2 at 0° C. The mixture wasconcentrated and lyophilized to afford crude product as white solid.ESI-MS, m/z 477 (MH)⁺.

Step 5: Synthesis ofN-(4-fluoro-3-methylphenyl)-1-(2-hydroxyethyl)-5-(2-(isopropylamino)-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(71)

HATU (60 mg, 0.16 mmol) was added to a solution of crude 71e (40 mg,0.08 mmol) in DMA (0.75 mL) at 0° C. After 20 min, tert-butylamine (10mg, 0.14) and DIPEA (25 mg, 0.19 mmol) in DMA (0.4 mL) were added. Thereaction mixture was stirred at rt for 20 hrs. The reaction mixture wasquenched with aqueous HCl (0.2N, 2 mL), then, extracted with EtOAc (10mL). The organic layer was washed with water and brine, and concentratedin vacuo. The residue was dissolved in DCM (1 mL) at 0° C., then, addedTFA (0.6 mL). After 4 hrs, the mixture was concentrated, and purified byreverse phase chromatography eluted with ACN and water, and dried usinglyophilization to afford the title product as white solid. ESI-MS, m/z418 (MH)⁺.

Example 72:5-(2-((1-amino-2-methyl-1-oxopropan-2-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1-(2-hydroxyethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 71, Step 5, using 2-amino-2-methylpropanamide. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 447 (MH)⁺.

Example 73:N-(4-fluoro-3-methylphenyl)-5-(2-(((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)amino)-2-oxoacetyl)-1-(2-hydroxyethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 71, Step 5, using 3-aminoadamantan-1-ol. The final product waspurified by reverse phase chromatography eluted with ACN and water anddried using lyophilization to afford the title products as white solids.ESI-MS, m/z 512 (MH)⁺.

Example 74:N-(4-fluoro-3-methylphenyl)-5-(2-(((1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using trans-4-aminoadamantan-1-ol. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 482 (MH)⁺.

Example 75:(S)-5-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using(S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 484 (MH)⁺.

Example 76:(R)-5-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using(R)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title products as whitesolids. ESI-MS, m/z 484 (MH)⁺.

Example 77:5-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)amino)-2-oxoacetyl)-N-(6-fluoropyridin-3-yl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 5, Step 5, using 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine.The final product was purified by reverse phase chromatography elutedwith ACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 471 (MH)⁺.

Example 78: Synthesis of(R)—N-(4-fluoro-3-methylphenyl)-5-(2-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using D-tert-leucinol. The final product was purifiedby reverse phase chromatography eluted with ACN and water and driedusing lyophilization to afford the title products as white solids.ESI-MS, m/z 432.2 (MH)⁺.

Example 79: Synthesis of5-(2-((1-(2H-tetrazol-5-yl)ethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 1-(2H-tetrazol-5-yl) ethan-1-amine. The finalproduct was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title products aswhite solids. ESI-MS, m/z 428 (MH)⁺.

Example 80: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-((3-methyl-1-(2H-tetrazol-5-yl)butyl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 3-methyl-1-(2H-tetrazol-5-yl)butan-1-amine. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 470 (MH)⁺.

Example 81: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-((2-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using2-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)propan-1-amine. The finalproduct was purified by flash chromatography on silica gel eluted withethyl acetate and hexane to afford the title products as white solids.ESI-MS, m/z 470 (MH)⁺.

Example 82: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-((1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 1-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-amine.The final product was purified by flash chromatography on silica geleluted with ethyl acetate and hexane to afford the title products aswhite solids. ESI-MS, m/z 470 (MH)⁺.

Example 83: Synthesis of5-(2-((cyclopropyl(5-methylthiazol-2-yl)methyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using cyclopropyl(5-methylthiazol-2-yl)methanamine.The final product was purified by reverse phase chromatography elutedwith ACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 483 (MH)⁺.

Example 84: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-((2-(5-methylthiazol-2-yl)propan-2-yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using 2-(5-methylthiazol-2-yl)propan-2-amine. Thefinal product was purified by flash chromatography on silica gel elutedwith ethyl acetate and hexane to afford the title products as paleyellow solids. ESI-MS, m/z 471 (MH)⁺.

Example 85: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-(((3-methyl-1,2,4-oxadiazol-5-yl)(tetrahydro-2H-pyran-4-yl)methyl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide

The title compounds were prepared following the procedure described inExample 2, Step 5, using(3-methyl-1,2,4-oxadiazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanamine Thefinal product was purified by flash chromatography on silica gel elutedwith ethyl acetate and hexane to afford the title products as whitesolids. ESI-MS, m/z 512 (MH)⁺.

Example 115: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1-(2-fluoroethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis of ethyl1-(2-fluoroethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (115b)

The title compounds were prepared following the procedure described inExample 71, Step 1 using 1-fluoro-2-iodoethane instead of(2-bromoethoxy)(tert-butyl)dimethylsilane. The final product waspurified by flash chromatography on silica gel (EtOAc/Hexanes 0˜100%) aswhite solid (3 g): ESI-MS, m/z 214.1 (MH)⁺.

Step 2: Synthesis ofN-(4-fluoro-3-methylphenyl)-1-(2-fluoroethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(115c)

The title compounds were prepared following the procedure described inExample 71, Step 2. The final product was purified by flashchromatography on silica gel (EtOAc/Hexanes 0˜100%) as yellow solid (3g): ¹HNMR (300 MHz, CDCl₃) δ 7.46 (dd, 1H, J=2.4 & 6.6 Hz), 7.24-7.28(m, 1H), 6.95 (dd, 1H, J=8.7 & 9.3 Hz), 6.42 (s, 1H), 4.68 (dd, 1H,J=4.2 & 5.1 Hz), 4.53 (dd, 1H, J=4.5 & 5.4 Hz), 4.13 (dd, 1H, J=4.8 &5.4 Hz), 4.04 (dd, 1H, J=4.8 & 5.7 Hz), 2.49 (s, 3H), 2.29 (s, 3H), 2.27(s, 3H); ESI-MS, m/z 293.1 (MH)⁺.

Step 3: Synthesis of ethyl2,2-difluoro-2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1-(2-fluoroethyl)-3,5-dimethyl-1H-pyrrol-2-yl)acetate(115d)

Ethyl 2-bromo-2,2-difluoroacetate (0.6 mL) was added to a mixture of115c (0.6 g, 2.1 mmol) and Cu (0.6 g, 9.4 mmol) in DMSO (10 mL) at rt.The mixture was flushed with argon, then, heated at 60° C. for 24 hrs.After cooled to rt, the reaction mixture was diluted with EtOAc, washedwith aqueous NH₄Cl and brine. The organic layer was dried over Na₂SO₄,filtered, concentrated in vacuo, and purified by flash chromatography onsilica gel (EtOAc/Hexanes 0˜100%) to afford the product as white solid(0.6 g, 70%). ESI-MS, m/z 415.1 (MH)⁺.

Step 4: Synthesis of2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1-(2-fluoroethyl)-3,5-dimethyl-1H-pyrrol-2-yl)-2-oxoaceticacid (115e)

NaOH (2 N, 3 mL) was added to a solution of 115d (0.2 g, 0.48 mmol) inMeOH (3 mL) at 0° C. The mixture was warmed to rt for 20 hrs. Thereaction mixture was diluted with EtOAc, cooled with ice-water andcarefully neutralized with aqueous HCl (0.5 N) to pH˜2. The organiclayer was washed with brine, concentrated and dried to afford crudeproduct 115e as white solid: ESI-MS, m/z 365.1 (MH)⁺.

Step 5: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1-(2-fluoroethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

HATU (90 mg, 0.24 mmol) was added to a solution of 115e (60 mg) in DMA(0.75 mL) at 0° C., then, a solution of tert-butylamine (20 mg, 0.28)and DIPEA (50 mg, 0.38 mmol) in DMA (0.4 mL) was added dropwise. Thereaction mixture was warmed to rt for 20 hrs. The reaction mixture wasquenched with aqueous HCl (0.2 N), and extracted with EtOAc. The organiclayer was washed with water and brine, concentrated in vacuo, then,purified by reverse phase chromatography eluted with ACN and water, anddried using lyophilization to afford the title product as white solid.ESI-MS, m/z 420.2 (MH)⁺.

Example 137: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(((1s,4s)-4-hydroxycyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

To a mixture of intermediate 66e from Example 66 (3.2 g, 9.63 mmol),cis-4-hydroxycyclohexylamine hydrochloride (1.61 g, 10.59 mmol) and HATU(4.39 g, 11.56 mmol) in DMF (40 mL) at ambient temperature was addedDIPEA (6.22 g, 48.15 mmol). After 2 h the reaction mixture was dilutedinto 1N HCl and extracted 3× EtOAc. The combined organics were washedsequentially with 1 N HCl, NaHCO₃ (sat), and brine, dried over Na₂SO₄,filtered and concentrated. The crude solids were concentrated from MeCNthen suspended in MeCN and warmed to 40° C. After 1 h the mixture wascooled to ambient temperature, filtered and washed with MeCN and theresultant solids were dried in vacuo. The solids were again suspended inMeCN and warmed to 40° C. After 1 h the mixture was cooled to ambienttemperature, filtered and washed with MeCN and the resultant solids weredried in vacuo to provide the title compound (2.52 g, 61%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 1H), 8.60 (d,J=7.5 Hz, 1H), 7.59 (d, J=6.9 Hz, 1H). 7.46 (m, 1H), 7.06 (t, J=9.3 Hz,1H), 4.38 (m, 1H), 3.75 (s, 3H), 3.68 (m, 2H), 2.31 (s, 3H), 2.20 (m,6H), 1.70-1.40 (m, 8H). ESI-MS, m/z 430.2 (MH)⁺.

Example 170: Synthesis of(R)—N-(2-fluoropyridin-4-yl)-1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxamide

The title compound was prepared following the procedure described inExample 2, substituting 2-fluoro-4-aminopyridine for4-fluoro-3-methylaniline in Step 2, and substituting(R)-1,1,1-trifluoropropan-2-amine for tert-butylamine in Step 5. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the titleproducts as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.06 (d, 1H, J=9.3Hz), 7.52 (s, 1H), 7.42 (d, 1H, J=6.1 Hz), 4.7-4.8 (m, 1H), 3.84 (s,3H), 2.4 (s, 3H), 2.31 (s, 3H), 1.4 (d, 3H, J=6.9 Hz). ESI-MS, m/z 415.1(MH)⁺.

Example 213: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compound was prepared following the procedure described inExample 2, Step 5, using (1r,4r)-4-amino-1-methylcyclohexan-1-ol. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the title productas a white solid. ¹H NMR (300 MHz, CD₃OD) δ 8.69 (d, J=7.5 Hz, 1H),7.59-7.42 (m, 2H), 7.00 (t, J=9.0 Hz, 1H), 3.86-3.81 (m, 4H), 2.38 (s,3H), 2.32 (s, 3H), 2.26 (s, 3H), 1.97-1.91 (m, 2H), 1.72-1.49 (m, 6H),1.24 (s, 3H). ESI-MS, m/z 444.2 (MH)⁺.

Example 228: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(((1s,4s)-4-hydroxy-1-methylcyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compound was prepared following the procedure described inExample 2, using (1s,4s)-4-amino-4-methylcyclohexan-1-ol in Step 5. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the title productas a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.4-7.5 (m, 2H), 6.99 (dd,1H, J=7.8, 9.3 Hz), 3.81 (s, 3H), 3.80 (br m, 1H), 2.38 (s, 3H), 2.36(s, 3H), 2.26 (s, 3H), 1.8-2.0 (m, 6H), 1.5-1.6 (m, 2H), 1.46 (s, 3H).ESI-MS, m/z 444.2 (MH)⁺.

Example 267: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(((1s,3s)-3-hydroxy-1-methylcyclobutyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compound was prepared following the procedure described inExample 2, using (1s,3s)-3-amino-3-methylcyclobutan-1-ol in Step 5. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the title productas a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.43-7.49 (m, 2H), 7.0 (dd,1H, J=8.7, 9.3 Hz), 4.1-4.2 (m, 1H), 3.82 (s, 3H), 2.5-2.6 (m, 2H), 2.38(s, 3H), 2.37 (s, 3H), 2.2-2.3 (m, 5H), 1.47 (s, 3H). ESI-MS, m/z 416(MH)⁺.

Example 273: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(((1r,4r)-4-hydroxy-1-methylcyclohexyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compound was prepared following the procedure described inExample 2, using (1r,4r)-4-amino-4-methylcyclohexan-1-ol in Step 5. Thefinal product was purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the title productas a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.4-7.5 (m, 2H), 6.99 (dd,1H, J=7.8, 9.3 Hz), 3.82 (s, 3H), 3.5-3.7 (m, 1H), 2.38 (s, 3H), 2.37(s, 3H), 2.2-2.3 (m, 2H), 1.5-1.8 (m, 6H), 1.42 (s, 3H). ESI-MS, m/z 445(MH)⁺.

Synthesis of Example Compounds 23-26, 28, 30-33, 35, 39-41, 44-46, 51,52, 54-58, 60-62, 68, 69, 86-114, 116-136, 138-169, 171-212, 214-227,229-266, 268-272, 274-359 (Structures Shown in Table 1)

Examples 23-26, 28, 30-33, 35, 39-41, 44-46, 51, 52, 54-58, 60-62, 68,69, 86-114, 119-129, 131-136, 138-169, 171-176, 181-193, 199-200,204-209, 211, 212, 214-221, 223, 231-240, 242-266, 268-272, and 274-359(structures shown in Table 1) were prepared in analogy to the proceduresdescribed above for Example 2, utilizing the appropriate aryl amine inStep 2, and requisite amine in Step 5. The observed MS data for theseExamples are shown in Table 1.

Example compounds 116-118, 130, 177-180, 194-198, 201-203, 210, 222,224-227, 229, 230, and 241 (structures shown in Table 1), bearing a1-(2-fluoroethyl) pyrrole moiety were prepared in analogy to theprocedures described above for Example 115, utilizing the appropriatearyl amine in Step 2, and requisite amine in Step 5. The observed MSdata for these Examples are shown in Table 1.

Synthesis of Example Compounds 360 and 361 (Structures Shown in Table 1)

These Example compounds bearing a 1-(2-hydroxyethyl) pyrrole moiety maybe prepared in analogy to the procedures described above for Example 50,utilizing the requisite amine in Step 5.

Example 362: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(5-fluoropyridin-2-yl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide(structure shown in Table 1)

The title compound may be prepared according to the procedure of Example2, utilizing 5-fluoro-2-aminopyridine in Step 2, and tert-butyl amine inStep 5.

Example 363: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-4-chloro-N-(4-fluoro-3-methylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (363a)

To a solution of 1,2-dimethyl-1H-pyrrole-3-carboxylic acid (1.0 g, 7.19mmol), 3-methyl-4-fluoroaniline (989 mg, 7.91 mmol) and HATU (3.28 g,8.63 mmol) in DMF (20 mL) was added DIPEA (3.76 mL, 21.57 mmol). After96 h, the reaction mixture was warmed to 50° C. After an additional 16h, the reaction mixture was cooled to ambient temperature, diluted withEtOAc and washed successively with 1N HCl, NaHCO₃ (sat), and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The crude residue was purified via flash chromatography on silica gel(EtOAc/hexanes 5-60%) to afford the title compound (690 mg, 39%) as anoff-white solid ESI-MS, m/z 247.2 (MH)⁺

Step 2: Synthesis of ethyl2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetate(363b)

To a solution of 363a (690 mg, 2.8 mmol) in DCM (30 mL) at 0° C. wasadded ethyl 2-chloro-2-oxoacetate (847 μL, 7.56 mmol). After 15 min,AlCl₃ (933 mg, 7.0 mmol) was added in several portions and then thereaction mixture was allowed to warm slowly to ambient temperature.After 16 h, the reaction mixture was quenched slowly with ice, dilutedwith water and separated. The aqueous layer was further extracted withDCM, then the combined organics were washed with water, NaHCO₃ (sat) andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified via flash chromatography on silica gel(EtOAc/hexanes 5-80%) to afford the title compound (600 mg, 62%) as anoff-white solid ESI-MS, m/z 347.1 (MH)

Step 3: Synthesis of ethyl2-(3-chloro-4-((4-fluoro-3-methylphenyl)carbamoyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetate(363c)

To a solution of 363b (600 mg, 1.73 mmol) in DMF (10 mL) was addedN-chlorosuccinimide (694 mg, 5.2 mmol). After 16 h, the reaction mixturewas diluted with EtOAc and washed successively with 2×1 N HCl, NaHCO₃(sat) and brine, dried over Na₂SO₄, filtered and concentrated. The cruderesidue was purified via flash chromatography on silica gel(EtOAc/hexanes 5-70%) to afford the title compound (400 mg, 61%) as anpale yellow solid ESI-MS, m/z 415.1 (MNa)⁺

Step 4: Synthesis of2-(3-chloro-4-((4-fluoro-3-methylphenyl)carbamoyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoaceticacid (363d)

To a solution of 363c (400 mg, 1.05 mmol) in MeOH (10 mL) was added 1 NNaOH (2.1 mL). After 2 h, the reaction mixture was diluted with 1 N HClto pH˜1 then concentrated three times from MeOH. Salts were trituratedwith DCM and the mixture was filtered and concentrated to afford thetitle compound (370 mg, quant) and an off-white solid ESI-MS, m/z 353.1(MH)⁺

Step 5: Synthesis5-(2-(tert-butylamino)-2-oxoacetyl)-4-chloro-N-(4-fluoro-3-methylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide(363)

To a solution of 363d (50 mg, 0.14 mmol), tert-butyl amine (12 mg, 0.16mmol), and HATU (64 mg, 0.17 mmol) in DMF (1 mL) was added DIPEA (73 μL,0.42 mmol). After 1 h the reaction mixture was diluted into 1 N HCl andextracted 3× with EtOAc. The combined organics were washed with 1 N HCl,NaHCO₃ (sat) and brine, dried over Na₂SO₄, filtered and concentrated.The crude residue was purified via reverse phase chromatography elutedwith ACN and water and dried using lyophilization to afford the titleproducts as white solids. ESI-MS, m/z 406.2 (MH)⁺.

Synthesis of Example Compounds 364-376 (Structures Shown in Table 1)

Examples 374-376 were prepared in analogy to the procedures describedabove for Example 363, utilizing the appropriate aryl amine in Step 1,and requisite amine in Step 5. The observed MS data for these Examplesare shown in Table 1.

Example 377: Synthesis ofN-(3,4-difluorophenyl)-4-methoxy-1,2-dimethyl-5-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)acetyl)-1H-pyrrole-3-carboxamide

Compound 377a was prepared in analogy to the procedures described abovefor Example 363, utilizing 3,4-difluoroaniline in Step 1.

Step 1: Synthesis of2-(4-((3,4-difluorophenyl)carbamoyl)-3-methoxy-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoaceticacid (377b)

To a solution of 377a (2.31 g, 6.0 mmol) in MeOH (20 mL) and THF (20 mL)was added 1 N NaOH (7 mL). After 2 h the reaction mixture wasconcentrated to remove organics, diluted with water and washed withEtOAc. The aqueous layer was acidified to pH˜1 using conc. HCl andextracted 3× with EtOAc. The combined organics were washed with brine,dried over Na₂SO₄, filtered and concentrated to afford the titlecompound (1.28 g, 60%) as a foamy tan solid which was taken forwardwithout further purification ESI-MS, m/z 353.1 (MH)⁺

Step 2: Synthesis ofN-(4-fluoro-3-methylphenyl)-4-methoxy-1,2-dimethyl-5-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)acetyl)-1H-pyrrole-3-carboxamide(377)

To a solution of 377b (50 mg, 0.14 mmol),1-(trifluoromethyl)cyclopropan-1-amine hydrochloride (24 mg, 0.15 mmol)and HATU (65 mg, 0.17 mmol) in DMF (1 mL) was added DIPEA (122 μL, 0.7mmol). After 2 h the reaction mixture was purified directly via reversephase HPLC eluted with ACN and water and dried using lyophilization toafford the title product as a white solid. ESI-MS, m/z 460.2 (MH)⁺.

Synthesis of Example Compounds 378-385 (Structures Shown in Table 1)

Examples 378-385 were prepared in analogy to the procedures describedabove for Example 377, utilizing the requisite amine in Step 2. Theobserved MS data for these Examples are shown in Table 1.

Example 386: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-2-chloro-N-(4-fluoro-3-methylphenyl)-1,4-dimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis of 2-chloro-1,4-dimethyl-1H-pyrrole-3-carboxylic acid(386a)

To a solution of 1,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.0 g, 7.19mmol) in THF (50 mL) at −78° C. was added LDA (7.9 mL, 15.8 mmol, 2 MTHF/benzene) dropwise over 20 min. After 2 h, a solution of NCS (1.15 g,8.63 mmol) in THF (20 mL) was added dropwise over 20 min and the coolingbath was removed. After 16 h, the reaction mixture was diluted with 1NHCl and extracted 3× EtOAc. The combined organics were washed with 2×water, NaHCO₃ (sat) and brine, dried over Na₂SO₄, filtered andconcentrated. The crude residue was purified via reverse phase HPLCeluting with ACN and water and dried using lyophilization to afford thetitle product (770 mg, 62%) as an off-white solid. ESI-MS, m/z 174.1(MH)⁺.

Step 2: Synthesis of2-chloro-N-(4-fluoro-3-methylphenyl)-1,4-dimethyl-1H-pyrrole-3-carboxamide(386b)

To a solution of 386b (770 mg, 4.44 mmol), 3-methyl-4-fluoroaniline (666mg, 5.32 mmol) and HATU (2.19 g, 5.77 mmol) in DMF (12 mL) was addedDIPEA (2.32 mL, 13.3 mmol). After 1 h, the reaction mixture was heatedto 50° C. After 5 h reaction mixture was cooled to ambient temperature,diluted with EtOAc and washed successively with 1 N HCl, NaHCO₃ (sat)and brine, dried over Na₂SO₄, filtered and concentrated. The cruderesidue was precipitated from EtOAc, filtered, and the solids werewashed with hexanes and dried in vacuo to afford the title product (750mg, 60%) as an off-white solid. ESI-MS, m/z 281.1 (MH)⁺.

Step 3: Synthesis of ethyl2-(5-chloro-4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3-dimethyl-1H-pyrrol-2-yl)-2-oxoacetate(386c)

To a solution of 386b (750 mg, 2.67 mmol) in DCM (20 mL) at 0° C. wereadded ethyl 2-chloro-2-oxoacetate (807 μL, 7.21 mmol) and AlCl₃ (890 mg,6.68 mmol). After 16 h additional quantities of ethyl2-chloro-2-oxoacetate (807 μL, 7.21 mmol) and AlCl₃ (890 mg, 6.68 mmol)were added. After 4 h, the reaction mixture was quenched with ice andwater, and separated. The aqueous layer was extracted twice with DCM.The combined organics were washed with water, NaHCO₃ (sat) and brine,dried over Na₂SO₄, filtered and concentrated. The crude residue waspurified via flash chromatography on silica gel (5-80% EtOAc/hexanes) toafford the title product (570 mg, 56%) as a yellow foam. ESI-MS, m/z381.2 (MH)⁺.

Step 4: Synthesis of2-(5-chloro-4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3-dimethyl-1H-pyrrol-2-yl)-2-oxoaceticacid (386d)

To a suspension of 386c (570 mg, 1.5 mmol) in MeOH (10 mL) was added 1NNaOH (3 mL) and a solution was formed. After 2 h the reaction mixturewas diluted with 1 N HCl and concentrated 3× from MeOH. The resultantsolids were suspended in DCM, filtered, and washed with DCM. The solidswere then dissolved in MeOH, filtered and concentrated to afford thetitle product (525 mg, 99%) as a tan solid. ESI-MS, m/z 353.1 (MH)⁺.

Step 5: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-2-chloro-N-(4-fluoro-3-methylphenyl)-1,4-dimethyl-1H-pyrrole-3-carboxamide(386)

To a solution of 386d (50 mg, 0.14 mmol), tert-butylamine (12 mg, 0.16mmol) and HATU (65 mg, 0.17 mmol) in DMF (1 mL) was added DIPEA (73 μL,0.42 mmol). After 2 h, the reaction mixture was purified directly viareverse phase HPLC eluting with ACN and water and dried usinglyophilization to afford the title product (33 mg, 58%) as an off-whitesolid. ESI-MS, m/z 430.2 (MNa)⁺.

Synthesis of Example Compounds 387-391 (Structures Shown in Table 1)

Examples 387-391 were prepared in analogy to the procedures describedabove for Example 386, utilizing the appropriate aryl amine in Step 2and requisite amine in Step 5. The observed MS data for these Examplesare shown in Table 1.

Example 392: Synthesis of3-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide

Step 1. Synthesis of 1-formylpiperidine-2-carboxylic acid (392a)

To a solution of piperidine-2-carboxylic acid (4.9 g, 38 mmol) in formicacid (30 mL) was added acetic anhydride (50 mL) at 0° C. The resultingmixture was stirred 0 to 5° C. for 4 h. LCMS showed the reaction wascomplete. The mixture was concentrated in vacuo to obtain crude product80a (7.1 g) as colorless oil. MS (ESI): mass calcd. for C₇H₁₁NO₃ 157.07,m/z found 158.1 [M+H]⁺.

Step 2. Synthesis of methyl 5,6,7,8-tetrahydroindolizine-1-carboxylate(392b)

To a solution of intermediate 392a (7.1 g, 45 mmol) in acetic anhydride(70 mL) was added methyl propiolate (5.04 g, 60 mmol). The resultingmixture was stirred at 120° C. for 2 h under N₂. MS showed the desiredproduct, and the reaction was concentrated in vacuo. The residue waspurified by column chromatography (EtOAc/petroleum ether: 0-10%) toobtain the title compound (1.4 g, 17%) as white solid. MS (ESI): masscalcd. for C₁₀H₁₃NO₂ 179.09, m/z found 179.8 [M+H]⁺.

Step 3. Synthesis of methyl3-(2-ethoxy-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate(392c)

To a solution of compound 392b (538 mg, 3 mmol) and ethyl2-chloro-2-oxoacetate (620 mg, 4.5 mmol) in DCM (15 mL), AlCl₃ (790 mg,6 mmol) was added slowly at 0° C. The resulting mixture was warmed to RTand stirred for 5 h. Water (20 mL) was added slowly, and the mixture wasextracted with DCM (3×20 mL), the combined organic extract was driedover Na₂SO₄, and concentrated. The residue was purified by columnchromatography (EtOAc/petroleum ether: 0-20%) to obtain the titlecompound (930 mg crude) as a colorless oil. MS (ESI): mass calcd. forC₁₄H₁₇NO₅ 279.11, m/z found 280.1 [M+H]⁺.

Step 4. Synthesis of2-(1-(methoxycarbonyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-oxoaceticacid (392d)

To a solution of 392c (930 mg, 3.3 mmol) in MeOH (30 mL) was added 1 NLiOH aq. (60 mL). The resulting mixture was stirred for 5 h at RT. Themixture was poured into ice water (30 mL) and acidified using 1 Naqueous HCl to pH=3. The resulting solid was isolated by filtration toobtain the titeld compound (530 mg, 63%) as white solid. MS (ESI): masscalcd. for C₁₂H₁₃NO₅ 251.08, m/z found 252.1 [M+H]⁺.

Step 5. Synthesis of methyl3-(2-(tert-butylamino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate(392e)

To a solution of 392d (500 mg, 2 mmol), HATU (1.1 g, 4 mmol), DIPEA (520mg, 4 mmol) in DCM (30 mL), 2-methylpropan-2-amine (500 mg, 2 mmol) wasadded. The resulting mixture was stirred for 2 h at rt. The mixture wasconcentrated and purified by column chromatography (EtOAc/petroleumether: 0-15%) to obtain the title compound (480 mg, 79%) as white solid.MS (ESI): mass calcd. for C₁₆H₂₂N₂O₄ 306.1, m/z found 307.1 [M+H]⁺.

Step 6. Synthesis of3-(2-(tert-butylamino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1-carboxylicacid (392f)

To a solution of 392e (480 mg, 1.6 mmol) in MeOH (20 mL), LiOH aq. (30mL) was added. The resulting mixture was stirred for 2 h at 80° C. Themixture was concentrated and water (30 mL) was added and acidified using1 N aqueous HCl to pH=3. The resulting solid was isolated by filtrationto obtain the title compound (340 mg, 74%) as white solid. MS (ESI):mass calcd. for C₁₅H₂₀N₂O₄ 292.14, m/z found 293.1 [M+H]⁺.

Step 7. Synthesis of3-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-5,6,7,8-Tetrahydroindolizine-1-carboxamide

To a solution of 392f (120 mg, 0.4 mmol), HATU (310 mg, 0.8 mmol), andEt₃N (520 mg, 4 mmol) in DCM (20 mL), 5-amino-2-fluorobenzonitrile (82mg, 1.5 mmol) was added. The resulting mixture was stirred for 13 h atRT. The mixture was concentrated and purified by column chromatography(EtOAc/petroleum ether: 0-10%) to obtain the title compound (14 mg, 9%)as white solid. MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₃ 410.18, m/z found411.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.74 (d, J=4.3 Hz,1H), 8.46 (d, J=8.3 Hz, 1H), 7.46 (dd, J=8.3, 4.5 Hz, 1H), 7.13 (s, 1H),4.43 (t, J=5.8 Hz, 2H), 3.21 (t, J=6.2 Hz, 2H), 2.06-1.91 (m, 4H), 1.47(s, 9H).

Example 393: Synthesis of3-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide

The title compound was prepared according to the procedure of Example392, substituting 4-fluoro-3-methylaniline for5-amino-2-fluorobenzonitrile in Step 7. MS (ESI): mass calcd. forC₂₂H₂₆FN₃O₃ 399.20, m/z found 401.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ8.40 (s, 1H), 7.61 (s, 1H), 7.51 (d, J=6.8 Hz, 1H), 7.31 (s, 1H), 6.98(t, J=9.0 Hz, 1H), 4.39 (t, J=6.0 Hz, 2H), 3.30 (t, J=6.4 Hz, 2H), 2.30(s, 3H), 2.06-1.95 (m, 2H), 1.95-1.80 (m, 2H), 1.47 (s, 9H).

Synthesis of Example Compounds 394-433 (Structures Shown in Table 1)

Examples 394-433 were prepared in analogy to the procedures describedabove for Example 392, utilizing the requisite amine in Step 5, and theappropriate aryl amine in Step 7. The observed MS data for theseExamples are shown in Table 1.

Example 434: Synthesis of3-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

The title compound was prepared according to the procedure of Example392, substituting methyl but-2-ynoate for methyl propionate in Step 2,and 4-fluoro-3-methylaniline for 5-amino-2-fluorobenzonitrile in Step 7.H NMR (400 MHz, CDCl3) δ 7.46 (d, J=6.2 Hz, 1H), 7.19 (s, 1H), 6.99 (t,J=9.1 Hz, 1H), 6.41 (s, 1H), 4.23 (t, J=5.8 Hz, 2H), 3.09 (t, J=6.2 Hz,2H), 2.47 (s, 3H), 2.30 (s, 3H), 1.95 (d, J=5.4 Hz, 2H), 1.85 (d, J=5.5Hz, 2H), 1.48 (s, 9H). MS (ESI): mass calcd. for C₂₃H₂₈FN₃O₃ 413.21, m/zfound 414.1 [M+H]⁺.

Example 435: Synthesis of3-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

The title compound was prepared according to the procedure of Example392, substituting methyl but-2-ynoate for methyl propionate in Step 2.MS (ESI): mass calcd. for C₂₃H₂₅FN₄O₃ 424.19, m/z found 425.1 [M+H]+. ¹HNMR (400 MHz, CDCl₃) δ 8.75 (d, J=4.2 Hz, 1H), 8.46 (d, J=8.4 Hz, 1H),7.46 (dd, J=8.2, 4.3 Hz, 1H), 6.43 (s, 1H), 4.23 (d, J=5.8 Hz, 2H), 3.30(t, J=6.1 Hz, 2H), 2.98 (s, 1H), 2.91 (s, 1H), 2.58 (s, 3H), 1.94 (dd,J=15.7, 6.7 Hz, 2H), 1.48 (s, 9H).

Example 444: Synthesis ofN-(4-fluoro-3-methylphenyl)-3-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoacetyl)-2-methyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

The title compound was prepared according to the procedure for Example434, utilizing 2-amino-2-methylpropan-1-ol in Step 5, and4-fluoro-3-methylaniline in Step 7, to provide a white solid. ¹H NMR(300 MHz, DMSO-d₆) δ 9.78 (s, 1H), 8.53-8.49 (m, 1H), 7.62-7.58 (m, 1H),7.49-7.45 (m, 1H), 7.08 (t, J=8 Hz, 2H), 4.51 (s, 1H), 4.24-4.20 (m,2H), 3.16 (d, J=8 Hz, 2H), 2.92-2.88 (m, 2H), 2.22 (s, 6H), 1.90-1.86(m, 2H), 1.76-1.72 (m, 2H), 1.12 (s, 6H). ESI-MS, m/z 430.1 (MH)⁺.

Synthesis of Example Compounds 436-443 and 445-488 (Structures Shown inTable 1)

Examples 436-488 were prepared in analogy to the procedures describedabove for Example 434, utilizing the requisite amine and the appropriatearyl amine for preparation of the required intermediates. The observedMS data for these Examples are shown in Table 1.

Example 489: Synthesis of3-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide

Step 1. Synthesis of 1-formylpiperidine-2-carboxylic acid (489a)

To a solution of piperidine-2-carboxylic acid (4.9 g, 38 mmol) in formicacid (30 mL) was added acetic anhydride (50 mL) at 0° C. The resultingmixture was stirred 0 to 5° C. for 4 h. LCMS showed the reaction wascomplete. The mixture was concentrated in vacuo to obtain crude product489a (7.1 g) as colorless oil. MS (ESI): mass calcd. for C₇H₁₁NO₃157.07, m/z found 158.1 [M+H]⁺.

Step 2. Synthesis of ethyl 5,6,7,8-tetrahydroindolizine-1-carboxylate(489b)

To a solution of intermediate 489a (7.1 g, 45 mmol) in acetic anhydride(70 mL) was added ethyl propiolate (5.88 g, 60 mmol). The resultingmixture was stirred at 120° C. for 2 h under N₂. MS showed the desiredproduct, and the reaction was concentrated in vacuo. The residue waspurified by column chromatography (EtOAc/petroleum ether: 0-10%) toobtain the title compound (1.5 g, 17%) as white solid. MS (ESI): masscalcd. for C₁₁H₁₅NO₂ 193.11, m/z found 194.1[M+H]⁺.

Step 3. Synthesis of ethyl3-(2-ethoxy-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate(489c)

To a solution of compound 489b (579 mg, 3 mmol) and ethyl2-chloro-2-oxoacetate (620 mg, 4.5 mmol) in DCM (15 mL), AlCl₃ (790 mg,6 mmol) was added slowly at 0° C. The resulting mixture was warmed to RTand stirred for 5 h. Water (20 mL) was added slowly, and the mixture wasextracted with DCM (3×20 mL), the combined organic extract was driedover Na₂SO₄, and concentrated. The residue was purified by columnchromatography (EtOAc/petroleum ether: 0-20%) to obtain the titlecompound (967 mg crude) as a colorless oil. MS (ESI): mass calcd. forC₁₄H₁₇NO₅ 293.13, m/z found 294.1 [M+H]. ¹H NMR (400 MHz, CDCl₃) δ 7.68(s, 1H), 4.50-4.36 (m, 4H), 4.29 (q, J=7.1 Hz, 2H), 3.18 (t, J=6.3 Hz,2H), 2.02-1.97 (m, 2H), 1.94-1.80 (m, 2H), 1.43 (t, J=7.1 Hz, 3H), 1.36(t, J=7.1 Hz, 3H).

Step 4. Synthesis of ethyl2-chloro-3-(2-ethoxy-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate(489d)

To a solution of compound 489c (967 mg, 3.3 mmol) in CH₃COOH (25 mL),CF₃SO₃H (2.3 mg, 0.015 mmol) and NCS (661 mg, 4.95 mmol) was added at 0°C. The resulting mixture was warmed to RT and stirred overnight. Water(100 mL) was added slowly, and the mixture was extracted with CH₃COOEt(3×50 mL), the combined organic extract was dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography(EtOAc/petroleum ether: 0-10%) to obtain the title compound (252 mg) asa light yellow solide. MS (ESI): mass calcd. for C₁₅H₁₅ClNO₅ 327.09, m/zfound 327.9 [M+H]⁺

Step 5. Synthesis of2-(2-chloro-1-(ethoxycarbonyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-oxoaceticacid (489e)

To a solution of 489d (252 mg, 0.77 mmol) in MeOH (10 mL) was added 1 NLiOH aq. (20 mL). The resulting mixture was stirred for 5 h at RT. Themixture was poured into ice water (30 mL) and acidified using 1 Naqueous HCl to pH=3. The resulting solid was isolated by filtration toobtain the titeld compound (219 mg, 95%) as white solid. MS (ESI): masscalcd. for C₁₃H₁₄ClNO₅ 299.06, m/z found 300.1 [M+H]⁺.

Step 6. Synthesis of ethyl3-(2-(tert-butylamino)-2-oxoacetyl)-2-chloro-5,6,7,8-tetrahydroindolizine-1-carboxylate(489f)

To a solution of 489e (219 mg, 0.73 mmol), BOP-Cl (280 mg, 1.1 mmol),DIPEA (194 mg, 1.5 mmol) in DCM (15 mL), 2-methylpropan-2-amine (64 mg,0.88 mmol) was added. The resulting mixture was stirred for 2 h at rt.The mixture was concentrated and purified by column chromatography(EtOAc/petroleum ether: 0-15%) to obtain the title compound (223 mg,86%) as white solid. MS (ESI): mass calcd. for C₁₇H₂₃ClN₂O₄ 354.1, m/zfound 355.0 [M+H]⁺.

Step 7. Synthesis of3-(2-(tert-butylamino)-2-oxoacetyl)-2-chloro-5,6,7,8-tetrahydroindolizine-1-carboxylicacid (489 g)

To a solution of 489f (223 mg, 0.63 mmol) in MeOH (20 mL), 1 N LiOH aq.(30 mL) was added. The resulting mixture was stirred for 2 h at 80° C.The mixture was concentrated and water (30 mL) was added and acidifiedusing 1 N aqueous HCl to pH=3. The resulting solid was isolated byfiltration to obtain the title compound (174 mg, 85%) as white solid. MS(ESI): mass calcd. for C₁₅H₁₉ClN₂O₄ 326.1, m/z found 327.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 12.57 (s, 1H), 8.25 (s, 1H), 4.19 (t, J=5.4 Hz,2H), 3.03 (t, J=6.0 Hz, 2H), 1.89 (brs, 2H), 1.76 (br s, 2H), 1.33 (s,9H).

Step 8. Synthesis of3-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-5,6,7,8-Tetrahydroindolizine-1-carboxamide

To a solution of 489 g (110 mg, 0.3 mmol), BOP-Cl (129 mg, 0.5 mmol),and Et₃N (91 mg, 0.9 mmol) in DCM (20 mL), 4-fluoro-3-methylaniline (42mg, 1.5 mmol) was added. The resulting mixture was stirred for 13 h atRT. The mixture was concentrated and purified by column chromatography(EtOAc/petroleum ether: 0-10%) to obtain the title compound (35 mg, 73%)as white solid. MS (ESI): mass calcd. for C₂₂H₂₅ClFN₃O₃ 433.1, m/z found433.7 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1H), 8.30 (s, 1H),7.60 (dd, J=7.0, 2.2 Hz, 1H), 7.54-7.46 (m, 1H), 7.10 (t, J=9.2 Hz, 1H),4.23 (t, J=6.0 Hz, 2H), 2.93 (t, J=6.2 Hz, 2H), 2.22 (d, J=1.6 Hz, 3H),1.97-1.87 (m, 2H), 1.81-1.71 (m, 2H), 1.34 (s, 9H).

Example 492: Synthesis of2-chloro-N-(3,4-difluorophenyl)-3-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide

The title compound was prepared according to the procedure for Example489, utilizing 2-amino-2-methylpropan-1-ol in Step 6, and3,4-difluoroaniline in Step 8, to provide a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 10.19 (s, 1H), 8.14 (s, 1H), 7.84-7.80 (m, 1H),7.75-7.40 (m, 2H), 4.87-4.84 (m, 1H), 4.25-4.21 (m, 2H), 3.45 (s, 2H),2.93-2.90 (m, 2H), 1.94-1.90 (m, 2H), 1.79-1.74 (m, 2H), 1.29 (s, 6H).ESI-MS, m/z 454.1 (MH)⁺.

Synthesis of Example Compounds 489-491 and 493-534 (Structures Shown inTable 1)

Examples 489-534 were prepared in analogy to the procedures describedabove for Example 489, utilizing the requisite amine for Step 6, and theappropriate aryl amine in Step 8. The observed MS data for theseExamples are shown in Table 1.

Example 535: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide

The title compound was prepared according to the procedure of Example392, substituting proline for piperidine-2-carboxylic acid in Step 1,and substituting 4-fluoro-3-chloroaniline for5-amino-2-fluorobenzonitrile in Step 7. MS (ESI): mass calcd. forC₂₀H₂₁ClFN₃O₃ 405.13, m/z found 406.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.29 (s, 1H), 7.92 (d, J=6.6 Hz, 1H), 7.62 (s, 1H), 7.35 (d, J=8.6 Hz,2H), 7.14 (d, J=8.7 Hz, 1H), 4.39 (t, J=7.3 Hz, 2H), 3.24 (t, J=7.6 Hz,2H), 2.69-2.57 (m, 2H), 1.47 (s, 9H).

Example 536: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide

Step 1. Synthesis of formylproline (536a)

To a solution of proline (10.3 g, 89 mmol) in formic acid (60 mL) wasadded acetic anhydride (100 mL) at 0° C. The resulting mixture wasstirred 0 to 5° C. for 4 h. LCMS showed the reaction was complete. Themixture was concentrated in vacuo to obtain crude product 536a (12 g) ascolorless oil. MS (ESI): mass calcd. for C₆H₉NO₃ 143.03, m/z found 144.1[M+H]⁺.

Step 2. Synthesis of methyl 2,3-dihydro-1H-pyrrolizine-7-carboxylate(536b)

To a solution of intermediate 536a (12 g, 84 mmol) in acetic anhydride(120 mL) was added methyl propiolate (10.58 g, 126 mmol). The resultingmixture was stirred at 120° C. for 2 h under N₂. MS showed the desiredproduct, and the reaction was concentrated in vacuo. The residue waspurified by column chromatography (EtOAc/petroleum ether: 0-10%) toobtain the title compound (2.5 g, 18%) as white solid. MS (ESI): masscalcd. for C₉H₁₁NO₂ 165.08, m/z found 165.8 [M+H].

Step 3. Synthesis of methyl5-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylate (536c)

To a solution of compound 536b (2.5 g, 15 mmol) and ethyl2-chloro-2-oxoacetate (3 g, 7.5 mmol) in DCM (50 mL), AlCl₃ (790 mg, 6mmol) was added slowly at 0° C. The resulting mixture was warmed to RTand stirred for 5 h. Water (80 mL) was added slowly, and the mixture wasextracted with DCM (3×50 mL), the combined organic extract was driedover Na₂SO₄, and concentrated. The residue was purified by columnchromatography (EtOAc/petroleum ether: 0-20%) to obtain the titlecompound (1.6 g, crude) as a colorless oil. MS (ESI): mass calcd. forC₁₃H₁₅NO₅ 265.10, m/z found 266.1 [M+H]⁺.

Step 4. Synthesis of2-(7-(methoxycarbonyl)-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetic acid(536d)

To a solution of 536c (1 g, 3.7 mmol) in MeOH (30 mL) was added 1 N LiOHaq. (50 mL). The resulting mixture was stirred for 5 h at RT. Themixture was poured into ice water (200 mL) and acidified using 1 Naqueous HCl to pH=3. The resulting solid was isolated by filtration toobtain the title compound (640 mg, 71%) as white solid. MS (ESI): masscalcd. for C₁₁H₁₁NO₅ 237.06, m/z found 238.1 [M+H].

Step 5. Synthesis of methyl5-(2-(tert-butylamino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylate(536e)

To a solution of 536d (640 mg, 2.7 mmol), HATU (1.1 g, 4 mmol), Et₃N(1.09 g, 4 mmol) in DCM (30 mL), 2-methylpropan-2-amine (197 mg, 2 0.7mmol) was added. The resulting mixture was stirred for 2 h at rt. Themixture was concentrated and purified by column chromatography(EtOAc/petroleum ether: 0-30%) to obtain the title compound (567 mg,72%) as white solid. MS (ESI): mass calcd. for C₁₅H₂₀N₂O₄ 292.14, m/zfound 293.1 [M+H]⁺.

Step 6. Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylicacid (536f)

To a solution of 536e (567 mg, 1.9 mmol) in MeOH (20 mL), LiOH aq. (30mL) was added. The resulting mixture was stirred for 2 h at 75° C. Themixture was concentrated and water (30 mL) was added and acidified using1 N aqueous HCl to pH=3. The resulting solid was isolated by filtrationto obtain the title compound (454 mg, 84%) as white solid. MS (ESI):mass calcd. for C₁₄H₁₈N₂O₄ 278.13, m/z found 279.2 [M+H]⁺.

Step 7. Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide

To a solution of 536f (120 mg, 0.4 mmol), HATU (310 mg, 0.8 mmol), andEt₃N (520 mg, 4 mmol) in DCM (20 mL), 4-fluoro-3-methylaniline (187 mg,1.5 mmol) was added. The resulting mixture was stirred for 13 h at RT.The mixture was concentrated and purified by column chromatography(EtOAc/petroleum ether: 0-50%) to obtain the title compound (27 mg, 16%)as white solid. MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₃ 385.18 m/z found386.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.13 (s, 1H), 8.05(s, 1H), 7.68 (dd, J=7.1, 2.4 Hz, 1H), 7.57 (dd, J=7.7, 4.0 Hz, 1H),7.07 (t, J=9.2 Hz, 1H), 4.26 (t, J=7.2 Hz, 2H), 3.07 (t, J=7.5 Hz, 2H),2.23 (s, 3H), 1.38 (s, 9H).

Example 537: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide

The title compounds was prepared according to the procedure of Example536, substituting 2-amino-2-methylpropan-1-ol for tert-butylamine inStep 5. MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₄ 401.18 m/z found 401.9[M+H]⁺.

Example 538: Synthesis of5-(2-amino-2-oxoacetyl)-N-(3-chloro-4-fluorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-7-carboxamide

The title compound may be prepared according to the procedure of Example536, substituting ammonia for tert-butylamine in Step 5, and3-chloro-4-fluoroaniline in Step 7.

Example 539: Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-6-chloro-N-(4-fluoro-3-methylphenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide

Step 1. Synthesis of 2,3-dihydro-1H-pyrrolizine-7-carboxylic acid (539a)

To a solution of ethyl 2,3-dihydro-1H-pyrrolizine-7-carboxylate (12 g,67 mmol) in MeOH (150 mL) was added 3 N LiOH aq. (50 mL). The resultingmixture was stirred for 5 h at 80° C. The mixture was poured into icewater (400 mL) and acidified using 1 N aqueous HCl to pH=3. Theresulting solid was isolated by filtration to obtain the title compound(10.1 g, 100%) as white solid. MS (ESI): mass calcd. for C₈H₉NO₂ 151.06,m/z found 152.1 [M+H]⁺.

Step 2. Synthesis ofN-(4-fluoro-3-methylphenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide(539b)

To a solution of 539a (10.3 g, 68 mmol), BOP-Cl (26 g, 102 mmol), Et₃N(27.5 g, 272 mmol) in DCM (300 mL), 4-fluoro-3-methylaniline (8.5 g, 68mmol) was added. The resulting mixture was stirred for 20 h at rt. Themixture was concentrated and purified by column chromatography(EtOAc/petroleum ether: 0-50%) to obtain the title compound (6.5 g, 37%)as white solid. MS (ESI): mass calcd. for C₁₅H₁₅FN₂O 258.12, m/z found259.1 [M+H]⁺.

Step 3 Synthesis of ethyl2-(7-((4-fluoro-3-methylphenyl)carbamoyl)-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate(539c)

To a solution of compound 539b (6 g, 23 mmol) and ethyl2-chloro-2-oxoacetate (4.7 g, 35 mmol) in DCM (150 mL) was added slowlyat 0° C. The resulting mixture was warmed to RT and stirred for 5 h.Water (80 mL) was added slowly, and the mixture was extracted with DCM(3×50 mL), the combined organic extract was dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography(EtOAc/petroleum ether: 0-20%) to obtain the title compound (2.3 g and 4g crude) as yellow solid. MS (ESI): mass calcd. for C₁₉H₁₉FN₂O₄ 358.13,m/z found 359.1 [M+H].

Step 4 Synthesis of ethyl2-(6-chloro-7-((4-fluoro-3-methylphenyl)carbamoyl)-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate(539d)

To a solution of compound 539c (2.3 g, 6 mmol) in DMF (50 mL), NCS (1.03g, 67.8 mmol) was added at 25° C. The resulting mixture was stirred for25 h. Water (80 mL) was added, and the mixture was extracted with EA(3×50 mL), the combined organic extract was dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography(EtOAc/petroleum ether: 0-30%) to obtain the title compound (0.4 g and1.1 g crude) as brown solid. MS (ESI): mass calcd. for C₁₉H₁₈ClFN₂O₄392.09 m/z found 393.1 [M+H]⁺.

Step 5. Synthesis of2-(6-chloro-7-((4-fluoro-3-methylphenyl)carbamoyl)-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoaceticacid (539e)

To a solution of 539d (400 mg, 1.02 mmol) in MeOH (20 mL), NaOH aq. (30mL) was added. The resulting mixture was stirred for 2 h at 25° C. Themixture was concentrated and water (30 mL) was added and acidified using1 N aqueous HCl to pH=3. The resulting solid was isolated by filtrationto obtain the title compound (320 mg, 86%) as white solid. MS (ESI):mass calcd. for C₁₇H₁₄ClFN₂O₄ 364.06, m/z found 365.1 [M+H]⁺.

Step 7. Synthesis of5-(2-(tert-butylamino)-2-oxoacetyl)-6-chloro-N-(4-fluoro-3-methylphenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide

To a solution of 539e (50 mg, 0.14 mmol), BOP-Cl (70 mg, 0.27 mmol), andEt₃N (40 mg, 0.4 mmol) in DCM (10 mL), 2-methylpropan-2-amine (51 mg,0.7 mmol) was added. The resulting mixture was stirred for 13 h at RT.The mixture was concentrated and purified by column chromatography(EtOAc/petroleum ether: 0-50%) to obtain the title compound (12 mg, 20%)as white solid. MS (ESI): mass calcd. for C₂₁H₂₃ClFN₃O₃ 419.14 m/z found420.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.67 (s, 1H), 8.39 (s, 1H),7.60 (dd, J=7.1, 2.5 Hz, 1H), 7.53-7.45 (m, 1H), 7.10 (t, J=9.2 Hz, 1H),4.28 (t, J=7.3 Hz, 2H), 3.08 (t, J=7.5 Hz, 2H), 2.49-2.39 (m, 2H), 2.23(d, J=1.6 Hz, 3H), 1.35 (s, 9H).

Synthesis of Example Compounds 540-581 (Structures Shown in Table 1)

Examples 540-581 were prepared in analogy to the procedures describedabove for Example 539, utilizing the appropriate aryl amine in Step 2,and the requisite amine for Step 6. The observed MS data for theseExamples are shown in Table 1.

Example 582: Synthesis of6-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide

The title compound was prepared according to the procedure of Example392, substituting morpholine-3-carboxylic acid forpiperidine-2-carboxylic acid in Step 1. MS (ESI): mass calcd. forC₂₁H₂₁FN₄O₄ 412.15, m/z found 412.8 [M+H]⁺. H NMR (400 MHz, DMSO-d₆) δ8.85 (d, J=4.5 Hz, 1H), 8.75 (d, J=8.4 Hz, 1H), 8.29 (s, 1H), 7.98 (s,1H), 7.67 (dd, J=8.3, 4.4 Hz, 1H), 5.12 (s, 2H), 4.41 (s, 2H), 4.08 (t,J=4.9 Hz, 2H), 1.38 (s, 9H).

Example 583: Synthesis of6-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide

The title compound was prepared according to the procedure of Example392, substituting morpholine-3-carboxylic acid forpiperidine-2-carboxylic acid in Step 1, and substituting4-fluoro-3-methylaniline for 5-amino-2-fluorobenzonitrile in Step 7. MS(ESI): mass calcd. for C₂₁H₂₄FN₃O₄ 401.18, m/z found 401.9 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.13 (s, 1H), 8.10 (s, 1H), 7.65(d, J=7.0 Hz, 1H), 7.59-7.50 (m, 1H), 7.08 (t, J=9.2 Hz, 1H), 5.09 (s,2H), 4.32 (t, J=4.7 Hz, 2H), 4.00 (t, J=4.9 Hz, 2H), 2.23 (s, 3H), 1.39(s, 9H).

Synthesis of Example Compound 584 (Structures Shown in Table 1)

Example 584 was prepared in analogy to the procedures described abovefor Example 539, utilizing the appropriate aryl amine in Step 2.

Synthesis of Example Compounds 585 and 586 (Structures Shown in Table 1)

Examples 591 and 592 (structures shown in Table 1) may be prepared inanalogy to the procedures described above for Example 584.

Example 587: Synthesis of tert-butyl6-(2-(tert-butylamino)-2-oxoacetyl)-8-((4-fluoro-3-methylphenyl)carbamoyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Step 1. Synthesis of4-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylicacid (587a)

A mixture of 1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (23 g,100 mmol) in THF (200 mL) was added NaOH (1 mol/L in H₂O, 200 mL, 200mmol), followed by added Cbz-Cl (19 g, 110 mmol) dropwise. The mixturewas stirred at 25° C. for 4 hours. HCl (1N in H₂O) was added to pH=5,the organic phase was washed with H₂O, brine, dried and evaporated toafford product as yellow oil (25 g, 69%). MS (ESI): mass calcd. forC₁₈H₂₄N₂O₆ 364.16, m/z found 365.1 [M+H]⁺.

Step 2. Synthesis of 4-((benzyloxy)carbonyl)piperazine-2-carboxylic acid(587b)

A mixture of4-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylicacid 587a (25 g, 69 mmol) in EtOH (50 mL) was added HCl.EtOH (35%, 50mL). The mixture was stirred at 25° C. for 4 hours. The mixture wasevaporated to afford product as white solid (18 g, 100%). MS (ESI): masscalcd. for C₁₃H₁₆N₂O₄ 264.11, m/z found 265.1 [M+H]⁺.

Step 3. Synthesis of4-((benzyloxy)carbonyl)-1-formylpiperazine-2-carboxylic acid (587c)

The title compound was prepared from compound 587b following theprocedure described in Example 392, Step 1, using4-((benzyloxy)carbonyl)piperazine-2-carboxylic acid. Title product (20g, crude) as white solid was obtained. MS (ESI): mass calcd. forC₁₄H₁₆N₂O₅ 292.11, m/z found 293.1 [M+H].

Step 4. Synthesis of 2-benzyl 8-methyl3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (587d)

The title compound was prepared from 587c following the proceduredescribed in Example 392, Step 2, using4-((benzyloxy)carbonyl)-1-formylpiperazine-2-carboxylic acid, to provide587d (16 g, 74%) as white solid. MS (ESI): mass calcd. for C₁₄H₁₆N₂O₅292.11, m/z found 293.1 [M+H]⁺.

Step 5. Synthesis of 2-benzyl 8-methyl6-(2-ethoxy-2-oxoacetyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate(587e)

To a solution of 587d (3.14 g, 10 mmol), ethyl 2-chloro-2-oxoacetate(2.04 g, 15 mmol) in DCM (15 mL) was stirred for 15 h. 20 mL water wasadded slowly, and the mixture was extracted with DCM (3×20 mL), driedover Na₂SO₄, concentrated. The residue was purified by FCC (EA/PE:0-20%) to obtain the title compound (2 g, 48%) as colorless oil. MS(ESI): mass calcd. for C₂₁H₂₂N₂O₇ 414.14, m/z found 415.1 [M+H].

Step 6. Synthesis of 2-(tert-butyl) 8-methyl6-(2-ethoxy-2-oxoacetyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate(587f)

A mixture of 587e (2 g, 4.8 mmol) in EtOH (20 mL) was added Boc₂O (1.09g, 5 mmol) and Pd/C (50 mg), the mixture was stirred under H₂ with aballoon for 20 min, then the mixture was filtered and evaporated toafford product as white solid (1.2 g, 67%). MS (ESI): mass calcd. forC₁₈H₂₄N₂O₇ 380.16, m/z found 381.1 [M+H]⁺.

Step 7. Synthesis of2-(2-(tert-butoxycarbonyl)-8-(methoxycarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-2-oxoaceticacid (587g)

The title compounds were prepared following the procedure described inExample 392, Step 4, using 2-(tert-butyl) 8-methyl6-(2-ethoxy-2-oxoacetyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate(587f). Title product (800 mg, 85%) as white solid was obtained. MS(ESI): mass calcd. for C₁₆H₂₀N₂O₇ 352.13, m/z found 353.1 [M+H]⁺.

Step 8. Synthesis of 2-(tert-butyl) 8-methyl6-(2-(tert-butylamino)-2-oxoacetyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate(587h)

The title compounds were prepared from compound 587g following theprocedure described in Example 392, Step 5. The title product (480 mg,75%) was obtained as yellow solid. MS (ESI): mass calcd. for C₂₀H₂₉N₃O₆407.21, m/z found 408.0 [M+H]⁺.

Step 9. Synthesis of2-(tert-butoxycarbonyl)-6-(2-(tert-butylamino)-2-oxoacetyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylicacid (587i)

The title compounds were prepared from compound 344h, following theprocedure described in Example 392, Step 6. The title product (400 mg,77%) was obtained as yellow solid. MS (ESI): mass calcd. for C₁₉H₂₇N₃O₆393.19, m/z found 394.0 [M+H]⁺.

Step 10. Synthesis of tert-butyl6-(2-(tert-butylamino)-2-oxoacetyl)-8-((4-fluoro-3-methylphenyl)carbamoyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

The title compounds were prepared from compound 587i following theprocedure described in Example 392, Step 6. The title product (280 mg,65%) was obtained as yellow solid. MS (ESI): mass calcd. for C₂₆H₃₃FN₄O₅500.24, m/z found 501.0 [M+H]⁺.

Example 588: Synthesis of6-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

To a solution of Example 587 (260 mg, 0.52 mmol) in EtOH (5 mL) wasadded 35% HCl in EtOH (5 mL), and the solution was stirred at 20° C. for1 h. The solution was evaporated and purified by preparative HPLC toafford the title compound as white solid (190 mg, 91%). MS (ESI): masscalcd. for C₂₁H₂₅FN₄O₃ 400.19, m/z found 401.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 10.02 (s, 1H), 8.14 (s, 2H), 8.07 (s, 1H), 7.64 (d, J=7.0 Hz,1H), 7.55 (br s, 1H), 7.09 (t, J=9.2 Hz, 1H), 4.43 (s, 2H), 4.34 (s,2H), 3.28 (s, 2H), 2.23 (s, 3H), 1.39 (s, 9H).

Example 589: Synthesis of6-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-(methylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

To a mixture of Example 588 (90 mg, 0.225 mmol) in DCM (5 mL) was addedEt₃N (0.5 mmol) and methanesulfonyl chloride (31 mg, 0.27 mmol), and themixture was stirred at 25° C. for 2 h and then evaporated in vacuo. Theresidue was purified by preparative HPLC to afford the title compound(20 mg, 21%) as white solid. MS (ESI): mass calcd. for C₂₂H₂₇FN₄O₅S478.17, m/z found 479.0 [M+H]⁺. H NMR (400 MHz, DMSO-d₆) δ 10.08 (s,1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.69 (d, J=5.6 Hz, 1H), 7.55 (brs, 1H),7.09 (t, J=9.2 Hz, 1H), 4.83 (s, 2H), 4.46 (s, 2H), 3.65 (s, 2H), 3.07(s, 3H), 2.24 (s, 3H), 1.39 (s, 9H).

Example 590: Synthesis of2-acetyl-6-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

To a mixture of Example 588 (90 mg, 0.225 mmol) in DCM (5 mL) was addedEt₃N (0.5 mmol) and acetyl chloride (18 mg, 0.225 mmol), and the mixturewas stirred at 25° C. for 2 h, and then evaporated in vacuo. The residuewas purified by preparative HPLC to afford the title compound as whitesolid (20 mg, 20%). MS (ESI): mass calcd. for C₂₃H₂₇FN₄O₄ 442.20, m/zfound 443.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.06-10.03 (m, 1H),8.13-8.09 (m, 2H), 7.69 (d, J=6.6 Hz, 1H), 7.56 (s, 1H), 7.09 (t, J=9.4Hz, 1H), 5.09-5.01 (m, 2H), 4.43-4.33 (m, 2H), 3.88 (br s, 2H), 2.24 (s,3H), 2.13 (d, J=8.4 Hz, 3H), 1.39 (s, 9H).

Synthesis of Example Compounds 591 and 592 (Structures Shown in Table 1)

Examples 591 and 592 (structures shown in Table 1) may be prepared inanalogy to the procedures described above for Example 590.

Synthesis of Example Compounds 593 and 594 (Structures Shown in Table 1)

Examples 593 and 594 (structures shown in Table 1) may be prepared inanalogy to the procedures described above for Example 392, utilizingazepane-2-carboxylic acid in Step 1.

Synthesis of Example Compounds 595-612 (Structures Shown in Table 1)

Examples 595-611, and 613-XXX were prepared in analogy to the proceduresdescribed above for Example

Examples 639, 641, 643, 645, 664, 666, 668, 670, 708, and 709 wereprepared in analogy to the procedures described above for Example 612,utilizing the requisite acids.

Example 612:5-(2-((1-acetyl-4-methylpiperidin-4-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-((4-methylpiperidin-4-yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide

To a mixture of Example 612a (110 mg, 0.5 mmol), Example 1 g (170 mg,0.5 mmol) and HATU (200 mg, 0.52 mmol) in DMF (1 mL) was added DIPEA at0° C. The reaction mixture was warmed to rt overnight. The reactionmixture was quenched with 0.5 N HCl and extracted with EtOAc. Thecombined extracts was washed with brine, and concentrated under vacuum.The residues was dissolved in DCM (2 mL), then, TFA (1.5 mL) was addedat 0° C. The mixture was warmed to rt for 2 hrs. The solvent wasevaporated and purified by reverse phase chromatography eluted with ACNand water and dried using lyophilization to afford the title products asTFA-salt pink solids. ESI-MS, m/z 551.3 (M+23)⁺.

Step 2: Synthesis of5-(2-((1-acetyl-4-methylpiperidin-4-yl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

To a solution of Example 612b (30 mg, 0.07 mmol), HATU (60 mg, 0.15mmol) and DIPEA (20 μL). in DMF (1 mL) was added AcOH (30 mg) 0° C. Thereaction mixture was stirred at rt for 20 hrs. The reaction mixture wasquenched with aqueous TFA (4%, 0.4 mL), and purified by reverse phasechromatography eluted with ACN and water, and dried using lyophilizationto afford the title product as white solid. ESI-MS, m/z 471.2 (MH)⁺.

Example 613:N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-((4-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide

DIPEA was added to a solution of 612b (30 mg, 0.07 mmol) andmethanesulfonyl chloride (20 mg, 0.17 mmol) in DCM (1 mL) at 0° C. After2 hrs at rt, the solvent was removed and the residue was purified byreverse phase chromatography eluted with ACN and water, and dried usinglyophilization to afford the title product as white solid. ESI-MS, m/z507.2 (MH)⁺. Examples 640, 642, 644, 665, 667 and 669 were prepared inanalogy to the procedures described above for Example 612, utilizing therequisite amines.

Example 614:N-ethyl-4-(2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetamido)-4-methylpiperidine-1-carboxamide

DIPEA was added to a solution of Example 612b (30 mg, 0.07 mmol) andisocyanatoethane (10 mg, 0.14 mmol) in DMA (1 mL) at 0° C. After 24 hrsat rt, the reaction mixture was purified by reverse phase chromatographyeluted with ACN and water, and dried using lyophilization to afford thetitle product as white solid. ESI-MS, m/z 500.3 (MH)⁺.

Example 681:N-(4-fluoro-3-methylphenyl)-5-(2-((4-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)tetrahydro-2H-pyran-4-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis of4-(2-(4-((4-fluoro-3-methylphenyl)carbamoyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetamido)tetrahydro-2H-pyran-4-carboxylicacid

To a mixture of 681a (100 mg, 0.5 mmol), 1g (170 mg, 0.5 mmol) and HATU(200 mg, 0.52 mmol) in DMF (1 mL) was added DIPEA at 0° C. The reactionmixture was warmed to rt overnight. The reaction mixture was dilutedwith water, and extracted with EtOAc (2×10 mL). The combined extractswas washed with water and brine, and concentrated under vacuum. Theresidues was dissolved in DCM (2 mL), then, TFA (1.2 mL) was added at 0°C. The mixture was warmed to rt for 4 hrs, then, the solvent wasevaporated and the residue was purified by reverse phase chromatographyeluted with ACN and water and dried using lyophilization to afford thetitle products as white solids. ESI-MS, m/z 460.2 (MH)⁺.

Step 2: SynthesisN-(4-fluoro-3-methylphenyl)-5-(2-((4-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)tetrahydro-2H-pyran-4-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

DIEPA (20 mg) was added to a solution of 681b (50 mg, 0.11 mmol),2-amino-2-methylpropan-1-ol (12 mg) and HATU (60 mg, 0.16 mmol) in DMFat 0° C. The mixture was warmed to rt for 12 hrs. The reaction wasquenched with aqueous HCl (0.2 N), and extracted with EtOAc. The organiclayer was washed with water and brine, concentrated in vacuo, then,purified by reverse phase chromatography eluted with ACN and water, anddried using lyophilization to afford the title product as white solid.ESI-MS, m/z 531.3 (MH)⁺.

Examples 605, 682, and 683 were prepared in analogy to the proceduresdescribed above for Example 681, utilizing the requisite amines.

Example 695 and 712:N-(4-fluoro-3-methylphenyl)-5-(2-(((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamideandN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-(((1R,2S,3R,4S)-2,3,4-trihydroxycyclopentyl)amino)acetyl)-1H-pyrrole-3-carboxamide

Step 1: Synthesis ofN-(4-fluoro-3-methylphenyl)-5-(2-(((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

The title compound was prepared from compound 695 following theprocedure described in Example 2 Step 5, using 695a. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title product as whitesolid. ESI-MS, m/z 488.2 (MH)⁺.

Step 2: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-oxo-2-(((1R,2S,3R,4S)-2,3,4-trihydroxycyclopentyl)amino)acetyl)-1H-pyrrole-3-carboxamide

HCl (2 N aqueous, 0.2 mL) was added to a solution of 695 (20 mg, 0.04mmol) in MeOH/CH₃CN (1/1, 1 mL) at rt. After 20 hrs at rt, the reactionmixture was purified by reverse phase chromatography eluted with ACN andwater and dried using lyophilization to afford the title product aswhite solid. ESI-MS, m/z 448.2 (MH)⁺.

Example 702 and 703:5-(2-(((3S,4R)-3,4-dihydroxy-1-methylcyclohexyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamideand5-(2-(((3R,4S)-3,4-dihydroxy-1-methylcyclohexyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis ofN-(4-fluoro-3-methylphenyl)-1,2,4-trimethyl-5-(2-((1-methylcyclohex-3-en-1-yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide

The title compound was prepared from compound 702b following theprocedure described in Example 2 Step 5, using 702a. The final productwas purified by reverse phase chromatography eluted with ACN and waterand dried using lyophilization to afford the title product as whitesolid. ESI-MS, m/z 426.2 (MH)⁺.

Step 2

AD-mix-beta (1 g) was added to a solution of 702b (60 mg) in tBuOH/water(1/1, 10 mL) at 0° C. The reaction was stirred at rt for 36 hrs. Thereaction was quenched with water and extracted with EtOAc. The organiclayer was washed with water and brine, concentrated in vacuo, andpurified by reverse phase chromatography eluted with ACN and water, anddried using lyophilization to afford 702 and 703 as white solid. ESI-MS,m/z 531.3 (MH)⁺.

Example 707 was prepared in the same procedure as described for Example614, using 1,2-difluoro-4-isocyanatobenzene instead of isocyanatoethane.

Example 722 and 723:N-(4-fluoro-3-methylphenyl)-5-(2-(((1S,3R)-3-hydroxy-1-methylcyclopentyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamideand N-(4-fluoro-3-methylphenyl)-5-(2-(((1S,3S)-3-hydroxy-1-methylcyclopentyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide

Step 1: Synthesis of (3S)-3-amino-3-methylcyclopentan-1-ol

NaBH₄ (0.1 g) was added to a solution of 722a (0.25 g, 1.2 mmol) in 6 mLof THF/MeOH (20/1) at 0° C. The reaction mixture was warmed to rt for 2hrs, then, concentrated. TFA (2 mL) was added to the residue in DCM (2mL) at 0° C. The reaction mixture was stirred at rt for 12 hrs, then,concentrated and purified by reverse phase chromatography eluted withACN and water and dried using lyophilization to afford the title productas white solid. ESI-MS, m/z 116.2 (MH)⁺.

Step 2: Synthesis of 722 and 723

DIPEA was added to a solution of 722b (30 mg, 0.07 mmol), HATU (125 mg,0.33 mmol) and 1g (90 mg, 0.27 mmol) in DMF (1 mL) at 0° C. The reactionmixture was stirred at rt for 20 hrs. The reaction mixture was quenchedwith aqueous TFA (4%, 0.4 mL), and purified by reverse phasechromatography eluted with ACN and water, and dried using lyophilizationto afford 722 and 723 product as white solid. ESI-MS, m/z 430.2 (MH)⁺.

Examples 729-759 were prepared in analogy to the procedures of Example434, utilizing the requisite amine and the appropriate aryl amine forpreparation of the required intermediates. The observed MS data forthese Examples are shown in Table 1.

Example I: Oral Composition of a Compounds of Formula (I), (Ia)-(Id), ora Pharmaceutically Acceptable Salt, Solvate, or Stereoisomer Thereof

To prepare a pharmaceutical composition for oral delivery, 400 mg ofcompound described herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof and the following ingredients are mixedintimately and pressed into single scored tablets.

Tablet Formulation

Tablet Formulation Ingredient Quantity per tablet (mg) compound 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Capsule Formulation Ingredient Quantity per capsule (mg) compound 200lactose spray dried 148 magnesium stearate 2

Example II: In Vitro Antiviral Assays

The anti-HBV activity of the Capsid Assembly Modulators (CAMs) wasevaluated in a cell based assay utilizing the human hepatoma cell lineHepAD38 (Ladner, S K., et al., 1998). HepAD38 cells were derived fromthe parental line, HepG2, that were stably transfected with a constructcontaining an HBV genome (genotype D, serotype ayw) under the control ofa tetracycline repressible CMV promoter. Upon removal of tetracycline,viral pre-genomic RNA (pgRNA) and mRNAs are expressed and infectiousviral particles are assembled and secreted into the culture mediumproviding a reliable, robust system to measure multiple steps of the HBVlife cycle. Disruption of capsid formation results in reduced levels ofDNA-containing virus particles that are released into the culturesupernatant. To quantify the effect of CAMs on HBV replication, wedeveloped a sensitive QPCR-based assay that measures extracellular HBVDNA levels upon treatment of HepAD38 cells with various concentrationsof test compounds.

HepAD38 cells were maintained in DMEM/F12 medium containing 10% FBS, 400μg/mL G418 and 0.3 μg/mL tetracycline (tet+ media) to maintainrepression of HBV replication. To evaluate each compound, HepAD38 cellswere seeded into 24-well collagen coated culture plates (CorningBioCoat) at a density of 200,000 cells per well in 1 mL of mediumwithout tetracycline (tet-media) and allowed to adhere overnight at 37°C., 5% CO₂ in a humidified incubator. The following day, media wasrefreshed and a dose range of each compound was prepared by performing 1log₁₀ serial dilutions in 100% DMSO at 200× the desired assayconcentration. Dilutions were then added to the cells resulting in afinal dose range of 1 μM to 10 μM and the plates were returned to theincubator. Following 7 days of incubation, culture supernatants wereharvested and HBV DNA levels were evaluated by QPCR and compared to thevehicle treated control wells (i.e. DMSO alone).

To quantify HBV DNA levels, cell culture supernatants were diluted 1:10in sterile, nuclease-free water (Gibco). The diluted supernatants weresubsequently added to a PCR master mix containing 1× Roche Light CyclerMaster Mix, 0.5 μM forward primer, 0.5 μM reverse primer (Fwd:5′-TTGGTGTCTTTCGGAGTGTG (SEQ ID NO 1); Rev: 5′-AGGGGCATTTGGTGGTCTAT (SEQID NO 2)), 0.2 μM Roche Universal Probe Library Probe 25. The volume wasbrought to 20 μL with nuclease-free water and amplification of the HBVtarget sequence was performed using a Roche LightCycler 480 QPCRinstrument. PCR extended out to 45 cycles with each cycle consisting ofa denaturation step at 95° C. for 10 sec., followed by an annealing stepat 60° C. for 10 sec. and a brief extension step at 72° C. for 1 sec.

Extracellular HBV DNA levels, expressed in copies/mL, were determined bycomparison to a standard curve (10²-10⁹ copies/mL) using the RocheLightCycler analysis software. These values were subsequently convertedto percent inhibition of HBV replication by dividing the HBV DNA levelsin the experimental samples with those obtained from the vehicle control(˜1-2×105 copies/mL). Potency, expressed as an EC₅₀ (the effectiveconcentration required to inhibit 50% of HBV replication), wascalculated from the dose-response curve using a 4-parameter non-linearregression analysis (GraphPad Prism). The nucleoside analog inhibitorentecavir was used as a positive control to validate each assay run. TheEC₅₀ value of entecavir in the HepAD38 assay was 0.5 nM, as previouslyreported in the literature.

Table 2 summarizes the antiviral activity of the exemplary compounds. A:EC₅₀>1 μM; B: EC₅₀ values between 0.5 μM and 1 μM, inclusive; C: EC₅₀values between 0.05 μM and 0.499 μM, inclusive; D: EC₅₀ values<0.05 M.NT=not tested. NA=not available.

TABLE 2 Summary of anti-HBV replication in HepAD38 cells. Anti- Anti-Anti- Anti- Anti- HBV HBV HBV HBV HBV Ex. EC₅₀ Ex. EC₅₀ Ex. EC₅₀ Ex.EC₅₀ Ex. EC₅₀ 1 D 2 D 3 D 4 D 5 C 6 D 7 D 8 D 9 D 10 D 11 D 12 D 13 D 14D 15 D 16 C 17 D 18 D 19 D 20 D 21 C 22 D 23 C 24 D 25 C 26 D 27 A 28 D29 B 30 A 31 C 32 A 33 A 34 A 35 A 36 D 37 D 38 D 39 B 40 B 41 D 42 D 43D 44 D 45 B 46 D 47 C 48 C 49 C 50 A 51 C 52 A 53 C 54 C 55 B 56 D 57 C58 B 59 D 60 D 61 C 62 D 63 D 64 D 65 D 66 D 67 D 68 A 69 B 70 D 71 A 72A 73 A 74 D 75 D 76 D 77 C 78 D 79 C 80 C 81 D 82 D 83 D 84 D 85 D 86 D87 D 88 D 89 D 90 D 91 D 92 C 93 C 94 D 95 D 96 D 97 D 98 D 99 C 100 A101 A 102 D 103 D 104 D 105 D 106 D 107 D 108 D 109 D 110 D 111 D 112 C113 D 114 D 115 D 116 D 117 C 118 D 119 D 120 B 121 D 122 D 123 C 124 D125 D 126 D 127 D 128 D 129 D 130 C 131 C 132 C 133 C 134 C 135 C 136 D137 D 138 D 139 D 140 D 141 D 142 D 143 D 144 D 145 D 146 D 147 D 148 D149 D 150 D 151 D 152 D 153 D 154 D 155 D 156 D 157 C 158 D 159 D 160 C161 D 162 C 163 A 164 B 165 D 166 D 167 D 168 C 169 D 170 D 171 D 172 D173 D 174 C 175 C 176 C 177 C 178 C 179 D 180 D 181 D 182 D 183 B 184 D185 B 186 C 187 A 188 C 189 D 190 D 191 D 192 B 193 A 194 C 195 D 196 C197 C 198 C 199 D 200 C 201 C 202 C 203 D 204 D 205 D 206 D 207 D 208 D209 D 210 D 211 D 212 D 213 D 214 D 215 D 216 D 217 D 218 D 219 D 220 D221 D 222 A 223 D 224 C 225 B 226 B 227 D 228 D 229 D 230 D 231 D 232 D233 C 234 D 235 NT 236 D 237 NT 238 D 239 B 240 C 241 D 242 C 243 D 244C 245 D 246 D 247 D 248 C 249 D 250 D 251 D 252 C 253 D 254 D 255 D 256C 257 C 258 D 259 D 260 D 261 D 262 D 263 D 264 D 265 C 266 C 267 D 268D 269 D 270 D 271 D 272 D 273 D 274 D 275 D 276 D 277 D 278 D 279 C 280D 281 D 282 D 283 D 284 D 285 D 286 D 287 D 288 D 289 D 290 D 291 D 292C 293 D 294 B 295 D 296 D 297 D 298 D 299 C 300 C 301 D 302 D 303 D 304D 305 A 306 D 307 D 308 B 309 C 310 D 311 D 312 D 313 D 314 D 315 D 316D 317 A 318 C 319 D 320 D 321 D 322 D 323 D 324 D 325 C 326 D 327 D 328C 329 B 330 D 331 D 332 D 333 D 334 D 335 D 336 D 337 B 338 B 339 B 340B 341 C 342 B 343 C 344 C 345 D 346 D 347 D 348 D 349 A 350 B 351 C 352C 353 C 354 D 355 D 356 D 357 D 358 D 359 D 360 NA 361 NA 362 NA 363 D364 D 365 D 366 D 367 D 368 C 369 D 370 D 371 C 372 D 373 D 374 D 375 D376 D 377 D 378 D 379 C 380 D 381 C 382 A 383 B 384 A 385 A 386 A 387 A388 A 389 A 390 C 396 C 397 C 398 C 399 C 400 C 401 A 402 C 403 C 404 C405 C 406 B 407 C 408 C 409 C 410 C 411 C 412 C 413 C 414 C 415 A 416 A417 C 418 C 419 A 420 C 421 A 422 A 423 A 424 C 425 C 426 C 427 C 428 C429 C 430 C 431 C 432 C 433 B 434 D 435 A 436 C 437 C 438 C 439 C 440 C441 D 442 D 443 D 444 D 445 D 446 C 447 D 448 D 449 C 450 C 451 C 452 D453 C 454 C 455 D 456 B 457 C 458 B 459 C 460 D 461 D 462 C 463 C 464 C465 D 466 C 467 B 468 C 469 B 470 B 471 B 472 A 473 B 474 B 475 B 476 A477 A 478 A 479 NA 480 NA 481 NA 482 NA 483 NA 484 NA 485 NA 486 NA 487NA 488 NA 489 D 490 D 491 D 492 D 493 D 494 D 495 D 496 D 497 C 498 C499 D 500 D 501 C 502 C 503 D 504 D 505 B 506 B 507 C 508 B 509 B 510 A511 C 512 B 513 C 514 C 515 D 516 C 517 C 518 C 519 C 520 D 521 A 522 A523 C 524 C 525 A 526 A 527 B 528 B 529 A 530 A 531 C 532 B 533 B 534 C535 D 536 D 537 C 538 NA 539 D 540 D 541 D 542 D 543 D 544 D 545 D 546 D547 C 548 D 549 B 550 D 551 C 552 D 553 D 554 D 555 C 556 C 557 D 558 D559 C 560 D 561 D 562 D 563 D 564 D 565 D 566 D 567 D 568 D 569 D 570 D571 C 572 D 573 C 574 B 575 B 576 C 577 A 578 B 579 B 580 D 581 D 582 A583 D 584 D 587 C 588 C 589 B 590 B 595 D 596 D 597 D 598 D 599 D 600 D601 D 602 D 603 D 604 D 605 D 606 D 607 D 608 D 609 D 610 D 611 D 612 D613 D 614 D 615 D 616 D 617 D 618 D 619 D 620 D 621 D 622 D 623 D 624 D625 D 626 D 627 D 628 D 629 D 630 D 631 D 632 D 633 D 634 D 635 D 636 D637 D 638 D 639 D 640 D 641 D 642 D 643 C 644 D 645 D 646 D 647 D 648 D649 D 650 C 651 D 657 D 658 D 659 D 660 D 661 D 662 D 663 D 664 D 665 D666 D 667 D 668 D 669 D 670 D 671 D 672 D 673 D 674 C 675 D 676 D 677 D678 D 679 D 680 D 681 D 682 D 683 D 684 D 685 D 686 D 687 D 688 D 689 D690 D 691 D 692 D 693 D 694 D 695 D 696 D 697 D 698 C 699 D 700 D 701 D702 D 703 D 704 D 705 D 706 D 707 D 708 D 709 D 710 D 711 D 712 D 713 D714 D 715 D 716 D 717 D 718 D 719 D 720 D 721 D 722 D 723 D 724 D 725 D726 D 727 D 728 D 729 C 730 C 731 D 732 C 733 D 734 D 735 C 736 D 737 D738 C 739 C 740 D 741 C 742 C 743 C 744 C 745 C 746 C 748 C 749 C 750 C751 C 752 C 753 C 754 C 756 C 757 C 758 C 759 C

Example III: In Vitro Cytotoxicity Assays

To evaluate antiviral selectivity, the cytotoxic activity of eachcompound was determined using a standard cell viability assay performedon the parental HepG2 cell line. Cell viability was determined bymeasuring the conversion of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tothe insoluble formazan salt crystal that occurs in live cells. Briefly,HepG2 cells were seeded in 96-well plates at a density of 20,000 cellsper well in EMEM+10% FBS (complete growth medium) and allowed to adhereovernight in a 37° C., 5% CO₂ humidified incubator. The next day, testagents were prepared by performing 8 half-log₁₀ serial dilutions in 100%DMSO at 200× the final desired concentration in the assay. Compoundswere tested over a range of concentrations from 30 μM to 1.0 nM in theassay. HepG2 cells were incubated in the presence of variousconcentrations of CAMs for 7 days in a 37° C., 5% CO₂ humidifiedincubator. At the completion of the 7-day incubation period, MTT reagentwas added to each well and the mixture was incubated for an additional3-4 hours. At the completion of the incubation period, all wells wereaspirated to remove the culture medium. The formazan crystals weresolubilized from the cell monolayers with 100% DMSO. Plates were brieflymixed on an orbital shaker and absorbance was measured at 492 nm using aPerkin-Elmer EnVision multi-label plate reader. All absorbance valueswere converted to a percentage of the signal obtained from the vehicletreated controls. Absorbance values at 492 nm are directly proportionalto the number of viable cells present in the sample. A CC₅₀ value(cytotoxic concentration that results in loss of 50% cell viability) wascalculated from the dose-response curve by 4-parameter, non-linearregression analysis using the GraphPad Prism software. The positivecontrol compound, staurosporine, reduced the viability of HepG2 cells ina dose-dependent manner (CC₅₀=100 nM).

Table 3 summarizes the cytotoxicity assay data in the hepatocyte cellline HepG2 for the example compounds. A: CC₅₀>30 μM; B: CC₅₀ valuesbetween 5 μM and 30 μM, inclusive; C: CC₅₀ values between 0.5 μM and4.99 μM, inclusive; D: CC₅₀ values<0.5 μM. NT=not tested. NA=notavailable.

TABLE 3 Summary of cytotoxicity results in HepG2 cells for examplecompounds. HepG2 HepG2 HepG2 HepG2 HepG2 Ex. CC₅₀ Ex. CC₅₀ Ex. CC₅₀ Ex.CC₅₀ Ex. CC₅₀ 1 A 2 A 3 B 4 A 5 A 6 A 7 A 8 A 9 A 10 B 11 A 12 A 13 A 14B 15 A 16 B 17 C 18 A 19 B 20 C 21 A 22 A 23 A 24 A 25 A 26 A 27 A 28 A29 A 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 A 38 A 39 A 40 C 41 C 42 A 43C 44 A 45 A 46 A 47 C 48 A 49 A 50 A 51 A 52 A 53 A 54 A 55 C 56 C 57 A58 A 59 A 60 A 61 A 62 A 63 A 64 B 65 A 66 A 67 A 68 A 69 A 70 A 71 A 72A 73 A 74 A 75 B 76 B 77 A 78 A 79 A 80 A 81 A 82 A 83 B 84 A 85 A 86 B87 A 88 B 89 A 90 B 91 A 92 A 93 A 94 A 95 A 96 A 97 A 98 A 99 A 100 B101 B 102 C 103 A 104 A 105 B 106 C 107 A 108 C 109 A 110 A 111 A 112 A113 A 114 A 115 A 116 A 117 A 118 A 119 A 120 A 121 A 122 A 123 A 124 B125 C 126 A 127 A 128 A 129 A 130 A 131 A 132 A 133 A 134 A 135 B 136 A137 A 138 C 139 A 140 A 141 A 142 A 143 A 144 A 145 A 146 A 147 A 148 A149 A 150 A 151 A 152 A 153 B 154 A 155 A 156 A 157 A 158 A 159 A 160 A161 A 162 A 163 A 164 A 165 A 166 A 167 A 168 A 169 A 170 A 171 A 172 A173 A 174 A 175 A 176 A 177 B 178 B 179 B 180 B 181 A 182 A 183 A 184 A185 A 186 A 187 A 188 A 189 A 190 A 191 A 192 A 193 A 194 A 195 A 196 A197 A 198 A 199 A 200 A 201 A 202 A 203 A 204 A 205 A 206 A 207 A 208 A209 A 210 A 211 A 212 B 213 A 214 A 215 A 216 B 217 A 218 B 219 A 220 B221 B 222 A 223 B 224 A 225 A 226 A 227 A 228 A 229 A 230 A 231 B 232 A233 A 234 A 235 NT 236 B 237 NT 238 A 239 A 240 A 241 A 242 A 243 B 244B 245 A 246 B 247 B 248 B 249 B 250 B 251 A 252 A 253 A 254 B 255 B 256B 257 B 258 B 259 A 260 B 261 C 262 B 263 A 264 B 265 A 266 A 267 A 268B 269 B 270 A 271 A 272 A 273 A 274 A 275 A 276 A 277 A 278 A 279 A 280A 281 B 282 A 283 B 284 A 285 A 286 A 287 A 288 A 289 B 290 A 291 A 292A 293 B 294 A 295 B 296 A 297 B 298 A 299 A 300 A 301 A 302 A 303 A 304B 305 A 306 A 307 A 308 A 309 A 310 E 311 A 312 B 313 B 314 B 315 A 316A 317 B 318 A 319 B 320 A 321 B 322 B 323 B 324 B 325 A 326 A 327 A 328A 329 A 330 A 331 A 332 A 333 A 334 A 335 A 336 B 337 B 338 A 339 A 340A 341 A 342 A 343 A 344 A 345 A 346 A 347 A 348 A 349 A 350 A 351 A 352A 353 A 354 A 355 A 356 A 357 A 358 A 359 A 360 NA 361 NA 362 NA 363 A364 B 365 A 366 A 367 B 368 A 369 A 370 A 371 A 372 C 373 C 374 C 375 A376 B 377 A 378 A 379 A 380 A 381 A 382 A 383 A 384 A 385 A 386 B 387 B388 B 389 B 390 A 391 A 392 B 393 A 394 A 395 C 396 B 397 B 398 A 399 A400 A 401 A 402 A 403 A 404 A 405 A 406 A 407 A 408 A 409 A 410 A 411 A412 B 413 A 414 A 415 A 416 A 417 A 418 A 419 A 420 A 421 A 422 A 423 B424 A 425 A 426 A 427 A 428 A 429 A 430 A 431 A 432 A 433 A 434 A 435 B436 A 437 A 438 A 439 A 440 B 441 B 442 B 443 B 444 B 445 B 446 B 447 B448 B 449 A 450 A 451 B 452 B 453 A 454 A 455 B 461 B 462 A 463 B 464 A465 B 466 A 467 A 468 A 469 B 470 B 471 A 472 A 473 A 474 A 475 A 476 B477 A 478 A 489 A 490 A 491 A 492 B 493 B 494 B 495 B 496 B 497 C 498 A499 A 500 B 501 B 502 A 503 A 504 B 505 A 506 B 507 A 508 A 509 A 510 A511 A 512 A 513 A 514 B 515 B 516 A 517 B 518 B 519 B 520 A 521 A 522 A523 B 524 B 525 A 526 A 527 C 528 C 529 A 530 A 531 A 532 C 533 A 534 B535 C 536 A 537 A 538 NA 539 B 540 A 541 A 542 A 543 A 544 A 545 B 546 A547 B 548 B 549 A 550 A 551 A 552 B 553 B 554 B 555 B 556 B 557 B 558 A559 A 560 A 561 A 562 B 563 B 564 B 565 B 566 B 567 A 568 B 569 A 570 A571 A 572 A 573 A 574 B 575 A 576 B 577 A 578 A 579 A 580 B 581 B 582 A583 A 584 B 585 NA 586 NA 587 A 588 B 589 A 590 A 595 A 596 A 597 A 598A 599 A 600 A 601 A 602 A 603 B 604 B 605 A 606 A 607 A 608 A 609 A 610A 611 A 612 A 613 A 614 A 615 A 616 A 617 A 618 A 619 A 620 A 621 A 622A 623 A 624 A 625 A 626 A 627 A 628 A 629 A 630 A 631 A 632 A 633 A 634A 635 A 636 A 637 A 638 A 639 A 640 B 641 A 642 B 643 A 644 B 645 A 646B 647 A 648 A 649 A 650 A 651 A 652 A 653 A 654 A 655 A 656 B 657 B 658B 659 A 660 A 661 B 662 A 663 A 664 A 665 B 666 A 667 C 668 A 669 A 670A 671 A 672 A 673 A 674 B 675 A 676 A 677 A 678 B 679 A 680 A 681 A 682A 683 A 684 A 685 A 686 C 687 B 688 A 689 A 690 A 691 A 692 A 693 A 694A 695 A 696 A 697 A 698 A 699 B 700 A 701 A 702 A 703 A 704 A 705 A 706A 707 C 708 A 709 A 710 A 711 A 712 A 713 A 714 A 715 B 716 A 717 B 718B 719 A 720 A 721 A 722 A 723 A 724 A 730 A 731 B 732 A 733 B 734 A 735B 736 B 737 A 738 A 739 A 740 A 741 A 742 A 743 A 744 A 745 A 746 A 748A 749 A 750 A 751 A 752 A 753 A 754 A 756 A 757 A 758 A 759 A

What is claimed is:
 1. A compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

wherein: Ring A is phenyl or pyridyl; each R¹¹ is independently halogen,C₁-C₆alkyl, or C₁-C₆haloalkyl; R¹² is hydrogen or C₁-C₆alkyl; R¹³ ishydrogen, halogen, or C₁-C₆alkyl; R¹⁴ is hydrogen, halogen, orC₁-C₆alkyl; R¹⁵ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆hydroxyalkyl; R¹⁶ is hydrogen or C₁-C₆alkyl; R¹⁷ is cyclohexyloptionally substituted with one, two, or three R⁷; n is 0-3; each R⁷ isindependently halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), —C(═O)OR^(b),—C(═O)NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkyl(aryl),—C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(cycloalkyl), or—C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(7a); each R^(7a) is independentlyoxo, halogen, —CN, —OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; each R^(a) is independentlyC₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three oxo, halogen, —CN, —OH, —OMe,—S(═O)Me, —S(═O)₂Me, —NH₂, —S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl; andeach R^(b) and R^(c) are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; whereineach alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂,—S(═O)₂NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl; or R^(b) and R^(c) are takentogether with the atom to which they are attached to form aheterocycloalkyl optionally substituted with one, two, or three oxo,halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O)₂Me, —NH₂, —S(═O)₂NH₂,—C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl.
 2. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R¹⁴ is hydrogen or C₁-C₆alkyl.
 3. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R¹⁵ is C₁-C₆alkyl.
 4. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R¹² is hydrogen.
 5. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R¹³ is hydrogen or C₁-C₆alkyl.
 6. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: Ring A is phenyl.
 7. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: each R¹¹ is independently halogen, or C₁-C₆alkyl.
 8. Thecompound of claim 1, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein: n is 1 or
 2. 9. The compound of claim 1,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R¹⁶ is hydrogen.
 10. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: each R⁷ is independently halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), —C(═O)OR^(b), —C(═O)NR^(b)R^(c), —C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, heterocycloalkyl, or heteroaryl;wherein each alkyl, heterocycloalkyl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(7a).
 11. The compoundof claim 1, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein: each R⁷ is independently halogen, —CN,—OH, —OR^(a), —NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆hydroxyalkyl; wherein each alkyl is independently optionallysubstituted with one, two, or three R^(7a).
 12. The compound of claim 1,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: each R^(7a) is independently halogen, —CN, —OH, —OR^(a),—NR^(b)R^(c), C₁-C₆alkyl, C₁-C₆haloalkyl, or heteroaryl.
 13. Thecompound of claim 1, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, selected from the group consisting of:


14. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, anda pharmaceutically acceptable excipient.
 15. A method of treatinghepatitis B in a subject, comprising administering to the subject acompound of claim 1, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof.
 16. The compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein: each R⁷ isindependently halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆hydroxyalkyl.
 17. The compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein: each R⁷ isindependently —OH or C₁-C₆alkyl.